Becoming aware of the shock (even ‘terror’?) of our EXISTENCE

The brute force of “Why is there something rather than nothing?”

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[Series Outline/Table of Contents]

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Question 7: Chemistry: active bio-information and  “struggle to survive”

 

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Source notes—references below by keyword refer to these multiple-quoted sources:

 

·         [Adami] = The Evolution of Biological Information: How Evolution Creates Complexity, from Viruses to Brains. // Adami, Christoph // PrincetonUP:2024. Kindle.

·         [Arias, Master] = The Master Builder: How the New Science of the Cell Is Rewriting the Story of Life . Alfonso Martinez Arias // Basic Books:2023. Kindle.

·         [Davies, Demon] = The Demon in the Machine --How hidden webs of information are solving the mystery of life. // Davies, Paul // Penguin:2019.

·         [Denton, Miracle] = The Miracle of the Cell. // Denton, Michael // DiscoveryInstitute:2020.

·         [Koonin] = The Logic of Chance: The Nature and Origin of Biological Evolution. // Koonin, Eugene // FTpress:2012.

·         [Living Systems] = Understanding Living Systems. // Noble, Raymond and Noble, Denis. // Cambridge University Press. Kindle Edition.

·         [Lynch, Origins] = The Origins of Genome Architecture. // Lynch, Michael // OxfordUP:2018.

·         [Prebiotic] = A Primer in Prebiotic Chemistry. // Albert C. Fahrenback and Henderson J Cleaves II // OUP:2024.

·         [Purpose] = Evolution "On Purpose": Teleonomy in Living Systems (Vienna Series in Theoretical Biology). // Corning, Peter A.; Kauffman, Stuart A.; Noble, Denis; Shapiro, James A.; Vane-Wright, Richard I. // MIT Press:2023. Kindle Edition

·         [Shapiro] = Evolution: A View from the 21st Century. Fortified. //Shapiro, James A.  // Cognition Press:2022. Kindle Edition.

·         [Transformations] = Transformations of Lamarckism: From Subtle Fluids to Molecular Biology (Vienna Series in Theoretical Biology), // Snait B. Gissis, Eva Jablonka, and Anna Zeligowski . // MIT:2011. Kindle Edition.

·         [Transitions] = The Major Transitions in Evolution Revisited (Vienna Series in Theoretical Biology). // Brett Calcott and Kim Sterelny,  // MIT:2011

·         [Walker] = Life as No One Knows It: The Physics of Life's Emergence. // Walker, Sara Imari. // Penguin Publishing Group:2024. Kindle Edition.

 

[Also—for practical and navigation reasons--when quoting source material, I have generally omitted THEIR use of sources, as they would include that in (parentheses). But—for the interested reader who wants to drill down on the sources’ sources, I have indicated WHERE they had referenced sources by LEAVING the parentheses, but REMOVING the contents. So, for example, (Goodman and Dorsey, 1948) became simply (---) in the quote. The interested reader could find the source of MY quote and then inspect it for THOSE (omitted) references.]

 

[AI usage disclosure: All of the text in this article was written by me, or by the authors of the individual quotes. I use AI (Claude) to summarize one chart, and identified it as being from Claude. I DID use AI heavily in producing the pretty charts (as a favor to the readers – smile). Although all the data used in the charts was reviewed and checked – and several iterations were required to verify them.]

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Question 7: Chemistry: active bio-information and  “struggle to survive”

 

“Why -- rather than nothing–

-- is there something – so ‘law-like’ , such that physics is possible,

-- of a scale that is incomprehensible in itself,

-- containing levels of complexity and patterns that stagger the mind,

-- that looks structured to allow ‘life’ as we know it, and

 

-- that contains uber-complex chemical structures / assemblies that contain chemical sub-units  that are so finely-tuned with OTHER chemical structures that they REPEATEDLY ‘act on’  one another, and with one another, in a coordinated fashion to maintain the whole, operate on a shared ‘clock’ in doing this, cooperate to respond to internal threats,  reproduce themselves, respond to external conditions  (e.g. threats, energy sources) as a unit, and occasionally MODIFY THEMSELVES to fulfill these requirements—when all other assemblies of chemical structures DO NOT,  and when we have no real explanation of how they got here nor an understanding of why they are STILL HERE!

 

Up to this point, “all” we have been confronted with is a universe (subset of SOMETHING) that has the building block elements necessary for life—but which are not alive themselves, and which actually do NOTHING without some ‘mixing and stirring up’.

 

And, because of ‘timing’ of cosmic factors, we have these building blocks in a narrow window of the universe in which ‘life’ COULD appear (and be sustained for a while).

 

But once our species ‘woke up, we noticed the amazing biosphere — we were surrounded by ‘living things’. And during our history, we discovered that there were single-celled living things that had been around much, much longer than we had, and which—without a ‘brain’ or ‘nervous system’—did all of the actions mentioned above—as ‘living cells’.

 

“The cell is a microscopic reaction vessel—a tiny ‘flask’. Despite its small size (and possibly because of it), a cell can carry out thousands of different reactions simultaneously, in a coordinated and highly regulated way, connected through positive and negative feedback mechanisms so that the cell is able to manufacture what it requires responsively. These feedback mechanisms allow the cell to behave as though it ‘knows what it’s doing’, responding to the environment to optimize its chances of success and survival, ultimately amplifying its own reproduction while relying on just a few basic inputs from the environment.” [Prebiotic pp.3-4]

 

We note here how ‘odd’ this ‘life’ is – maybe even worse in implications than the previous series of ‘oddness’.

 

I use the ‘maybe worse’ phrase deliberately. If ‘something’ itself ‘(the well-ordered universe we see) should not be/exist’ (nothing ‘should be’ the default, remember), then “life” as we see it now is does not even FIT here…

 

Life as we experience it now SEEMS to be built from all the physics and chemistry stuff, but SEEMS to be radically DISCONTINUOUS with that…

 

If you look at a jar of wiggling bacteria and then look at another jar containing the exact same amounts and sequences of chemicals that are in the bacteria—just ‘disassembled’ and mixed up—you would NOT assume they were related in any way.

 

Life just does not seem to ‘fit’ in a well-ordered and (reasonably) predictable physical universe.

 

·         Actions in physics ‘move’—but always on their way to eventual thermodynamic flat-lining.

·         Actions in chemistry ‘move’—but always on their way to equilibrium’s ‘stillness’. [auto-catalysis notwithstanding]

·         Actions in life ‘move’ but NEVER reach equilibrium and CONSTANTLY ‘outrun’ the 2^nd law of thermodynamics! Life runs ‘above’ those powerful processes.

 

 

But when a cell DIES, its corpse then takes its place in those natural, physical  pathways, decomposing and giving up all its stored energy to its surroundings.

 

“These metabolic reactions almost never reach equilibrium; in fact, if equilibrium in a cell were ever reached, then one might say the cell was dead.” [Prebiotic, p4.]

 

“One hint as to where a missing element may lie comes about from a simple observation. A living thing is not just a particular physico-chemical assembly, an aggregate of various molecular components synchronously functioning together like the cogs and wheels within a mechanical watch. A living system is better understood as an energized physico-chemical assembly (---), one which both stores and depends on a continuous supply of material and energy for its maintenance. If the material and energy supplies are cut off, the living system ceases to exist—it dies. Only then does that chemical aggregate behave as chemical aggregates normally do. That explains why life is so difficult to create. Simply, we still do not know how to generate dynamic energized systems of that kind.” [Purpose, pp. 259-260]

 

The seeming disconnect between living things and the non-living things that are USED by living things is so stark -- to me -- that it seems almost like another ‘something from nothing’ problem. [Not as severe as the main version perhaps, but still without any PLAUSIBLE origination process (efforts and spot successes in the OOL research area notwithstanding)]. It just ‘appears’ in geologic history, without any record of ancestry and without (so far) any demonstration in labs of PLAUSIBLE ancestry (brilliant work, IMO, but widely recognized as not-even-close-yet…).

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But to get back to base…

 

 

My descriptive statement above contains these phrases:

1.      That contains uber-complex chemical structures / assemblies, containing chemical sub-units that are so finely-tuned with OTHER chemical structures that they

a.       REPEATEDLY ‘act on’ one another, and with one another, in a coordinated fashion to maintain/grow the whole,

b.      Operate on a shared ‘clock’ in doing this,

c.       Cooperate to respond to internal threats (e.g. DNA and cellular repair mechanisms)

d.      Reproduce (when it senses that conditions are right for that)

e.       Respond to external conditions (e.g. threats, energy sources) as a unit, and

f.        Occasionally MODIFY THEMSELVES as needed to fulfill the requirements above…

2.      When all other assemblies of chemical structures DO NOT…

3.      And when we have no real explanation of how they got here…

4.      Nor how they are STILL here!

 

 

I am talking about the units we call ‘living CELLS’ , ranging from simple single cells (e.g. archaea, bacteria), generally (but not exclusively—see next question in the series) living independently of other cells, as well as cells as part of a multi-cellular unit (e.g. eukaryotes).

 

 

Nobody on the planet really knows what ‘life’ is, but most of the working definitions by researchers include these basic requirements:

1.      It ‘eats’ and grows: Metabolism (coordinated processes to sustain activity)

2.      It produces offspring: Information-based Reproduction/replication (e.g. DNA)

3.      It watches what is happening, and makes adjustments to the above as needed: Sensory and signaling mechanisms to detect/respond to threats (both internal and external threats).

 

My ‘characteristics’ list would fall into those categories like this:

·         Metabolism

o   “Repeatedly acting upon one another, and with one another, in a coordinated fashion to maintain the whole (would include internal growth and activity, digestion and waste processing; renewal of internal components—e.g. making proteins and managing energy resources)”

o   “Operating on a shared ‘clock’”

·         Information-based Reproduction/replication

o   “Reproduce themselves (when it senses that conditions are right for that)”

·         Sensory / signaling mechanisms to detect/respond

o   “Cooperate to respond to internal threats”

o   “Respond to external conditions (e.g. threats, energy sources) as a unit”

o   “Occasionally MODIFY THEMSELVES to fulfill these requirements”

 

 

The ACTIONS I describe below fall into one or more of those categories.

 

 

Okay, let me go through these elements, and give a piece of data or two, and perhaps a representative example or two…

 

 

 

ONE: uber-complex chemical structures / assemblies within the cell, as seen in SIZE, CONTENTS, and ACTIONS…

 

SIZE: The first thing to note here is how ‘odd’ the SIZE gap is between inorganic molecules and the smallest ‘life’ units (e.g. phages, virus, bacteria).

 

The largest naturally occurring INORGANIC molecules on record currently are packratite, vanarsite, ophirite, and morrisonite, ranging between 5.75kDa and 5.8kDa.

 

·         The smallest semi-living unit (the MS2 bacteriophage, a virus) has a single-stranded RNA molecule consisting of 3,569 nucleotides. At 330 Daltons per nucleotide, that sums up to 1.18MDa.

·         That single molecule is 202 times larger than packratite.

·         The total weight of the virus (since it contains 180+ proteins too) is 3.91MDa, which is 660 times larger than packratite.

 

This size gap gets much wider when we move to things that are classified as ‘fully alive’

 

The smallest cells that are considered to be alive, fall into 3 major categories:

 

1.      Obligate endosymbiont-- they are alive but are dependent on other organisms for some of their cellular functions.

2.      Parasitic symbiont– can reproduce and act independently, but mostly thrive inside hosts

3.      Free-living (able to live and reproduce independently of other cells/organisms)

 

 

(Types 2 and 3 we will discuss in the next ‘shock question’ – the social ontology of life as we know it.)

 

The smallest organisms found so far in these categories are these:

 

·         Obligate endosymbiont: Nasuia deltocephalinicol

·         Obligate endosymbiont: Nanoarchaeum equitans

·         Parasitic symbiont: Mycoplasma genitalium

·         Free-living: Pelagibacter ubique

 

When you compare the size of the largest inorganic molecule to the sizes of just the one chromosome molecule in each of these cells, the gap is a chasm:

The smallest living thing has a molecule over 12,000 times larger than packratite.

 

And our familiar ‘lab partner’  e.Coli’s genome is over half-a-million times larger.

 

This size gap is almost shocking—why are there NO objects in between these sizes?

 

Here is a chart of unit masses (not just molecules)—on a log scale!

Authorities recognize that the amount of COMPLEXITY of even the simplest of cells, requires SO MANY MOVING PARTS that it just cannot be reduced in size to that extent:

 

“Though the process by which life emerged continues to mystify, there is one facet of the process that is beyond doubt: the extraordinary degree of complexification that took place during that extended physico-chemical transformation. The conversion of some prebiotic chemical system, though of unknown identity, into simplest life would have involved an increase in size/mass of some nine orders of magnitude. [Molecular systems are typically of mass of ca. 10^(-21) g while that of a bacterium is ca. 10^(–12) g]. That’s a staggering change in both size and structural complexity—the equivalent of something the size of a coin growing into something the size of our planet. In fact, it seems reasonable to conclude that life’s unique nonmaterial characteristics must have emerged as a direct consequence of that extraordinary degree of complexification (Pross, 2013). So how can that process of complexification be explained? [Purpose, p. 259]

 

 

Although there are no ‘transitional forms’ in the record, the presumed path from non-life to life would have had to start with something AT LEAST 100 times larger than packratite.

 

Koonin [Koonin, p. 438] calculates values for a simplified ‘toy’ model, that deliberately over-inflates the rate of RNA replication and comes up with this statement:

 

“The requirements for the emergence of a primitive, coupled replication-translation system, which is considered a candidate for the breakthrough stage in this paper, are much greater. At a minimum, spontaneous formation of the following is required:

 

• Two rRNAs, with a total size of at least 1,000 nucleotides.

• Approximately 10 primitive adaptors of about 30 nucleotides each, for a total of approximately 300 nucleotides.

• At least one RNA encoding a replicase, about 500 nucleotides (low bound) required.

 

This totals out at 1,800 nucleotides, and at 330Da per, gives 594kDa as the smallest possible proto-life unit.

 

That is 100 times larger than packratite—and that is only the replicator ‘half-way’ point to what Koonin calls ‘bona fide biological entities’…

 

 

CONTENTS: Even the simplest of cells are filled with molecules in complex arrangements, of a wide variety of types, and with complex interactions—from Day One.

 

The oldest life forms that leave a fossil trace of its life in the geological record is reported as being around 3.2 BYA. And evidence of simpler life forms (stromatolites, but not fossils) is reported around 3.5 BYA.

 

“According to one view, a diverse assemblage of microbes, including cyanobacteria-like cells, had colonized the seas by -3.5 BYA (---). Some aspects of this interpretation of the fossil record have been questioned (---), but other signs of biological activity have been found in rocks from 3.4-3.8 BYA (---), and unambiguous fossils of filamentous organisms deposited around hydrothermal vents have been dated to 3.2 BYA (--). Thus, cellular life (as we know it) appears to have emerged from inorganic materials within a window of just a few hundred million years. [Lynch, Origins, p.2]

 

“The lack of distinctive morphological features renders the detailed taxonomic composition of the early fossil record quite uncertain, but the first 0.5-1.0 billion years of life appear to have been dominated by prokaryotes (simple cells lacking membrane-enclosed organelles, often referred to as bacteria), if not entirely restricted to them. … The first evidence of eukaryotes (cells with membrane-enclosed organelles, including a nucleus) appears in the form of putative diagnostic biomarkers of membrane components deposited in shale from -2.7 BYA (---). The first presumptive algal fossils date to -2.1 BYA (---), and many other fossils of unicellular eukaryotes with well-developed cytoskeletons date to 1.7-1.5 BYA (---). But despite this gradual addition of eukaryotic diversity, the biosphere continued to be dominated by unicellular and oligocellular (a few cell types) species for at least another billion years.” [Lynch, Origins, p.2]

 

And

 

“Stromalites are macroscopic sedimentary structures formed by microbial communities. As these communities grow, they deposit thin layers of (generally) calcareous (calcium based) minerals, or trap and bind calcareous sand grains, forming a stratified structure… Fossilized stromatolites appear through the fossil record, and indeed are the only fossil for almost 3 billion years of Earth history, but the oldest ones that have general scientific consensus date back to nearly 3.5 billion years ago, and are also found in Western  Australia. … Taking the appearance of liquid water as a necessary condition which can be constrained at 4.2 billion years ago, we can estimate that life emerged on Earth somewhere between 4.2 and at least 3.5 billion years ago—a 700 million-year window.” [Prebiotic, pp. 34-35]

 

 

These earliest life forms were already very complex and sophisticated:

 

“Given the presence of methanogenesis as early as 3.0BYA and photosynthesis as early as 2.8 BYA, we can conclude that the microbial world was quite sophisticated biochemically by this time, perhaps harboring the full repertoire of metabolic /molecular processes from which all subsequent cellular lineages were built.” [Lynch, Origins, p.2]

 

We can check this remark about ‘quite sophisticated’ by noting how the fossils were interpreted:

 

“Here we report the discovery of a population of large (up to about 300 micrometers in diameter) carbonaceous spheroidal microstructures in Mesoarchaean shales and siltstones of the Moodies Group, South Africa, the Earth's oldest siliciclastic alluvial to tidal-estuarine deposits. These microstructures are interpreted as organic-walled microfossils on the basis of petrographic and geochemical evidence for their endogenicity and syngeneity, their carbonaceous composition, cellular morphology and ultrastructure, occurrence in populations, taphonomic features of soft wall deformation, and the geological context plausible for life, as well as a lack of abiotic explanation falsifying a biological origin. These are the oldest and largest Archaean organic-walled spheroidal microfossils reported so far. Our observations suggest that relatively large microorganisms cohabited with earlier reported benthic microbial mats in the photic zone of marginal marine siliciclastic environments 3.2 billion years ago. “

[Javaux EJ, Marshall CP, Bekker A. “Organic-walled microfossils in 3.2-billion-year-old shallow-marine siliciclastic deposits”. Nature. 2010 Feb 18;463(7283):934-8.]

 

Notes:

1.       A 300 micrometer cell is 150-300 times larger than e.Coli…

2.       These were interpreted early as being versions of chemotrophic beggiatoacean gliding bacteria (can get up to 200 micrometers) and with photoautotrophic oscillatoriacean cyanobacteria (up to 10 micrometers).

3.       Schopf disputed the photo-synthetic interpretation and compared them to  non-photosynthetic cyanobacterium-like cells.

4.       If they are in the cyanobacteria family (photo or not) they were already VERY sophisticated: “Cyanobacteria are challenged by environmental stresses and internally generated reactive oxygen species that cause DNA damage. Cyanobacteria possess numerous E. coli-like DNA repair genes.[--] Several DNA repair genes are highly conserved in cyanobacteria, even in small genomes, suggesting that core DNA repair processes such as recombinational repair, nucleotide excision repair and methyl-directed DNA mismatch repair are common among cyanobacteria.”

5.       They have a wide range of genome sizes, ranging from 1,199 to 8,383 protein-coding genes (average of 3,580).

[Zamani Dahaj, Seyed Alireza. (2015). “A phylogenetic model to predict the patterns of presence and absence of genes in bacterial genomes and estimate the frequency of horizontal gene transfer.”]

6.       By comparison, e.Coli averages around 3,850 – so this is a large, complex cell – with no precursors in the fossil record so far….

 

 

 

 

And the current versions of these ‘simplest’ life forms are still ‘stupendously complex’:

 

“Whatever the minimal complexity for life may be, there is no doubt that even the simplest known life form is already stupendously complex. Indeed, life’s complexity is so daunting that it is tempting to give up trying to understand it in physical terms. A physicist may be able to give an accurate account of a hydrogen atom, or even a water molecule, but what hope is there for describing a bacterium in the same terms?” [Davies, Demon, pp. 82-83]

 

 “I’m fascinated by what makes organisms tick, what enables living matter to do such astounding things – things beyond the reach of non-living matter. Where does the difference come from? Even a humble bacterium accomplishes things so amazing, so dazzling, that no human engineer can match it. Life looks like magic, its secrets cloaked by a shroud of impenetrable complexity. Huge advances in biology over the past decades have served only to deepen the mystery. What gives living things that enigmatic oomph that sets them apart from other physical systems as remarkable and special? And where did all this specialness come from in the first place?” [Davies, Demon, pp. 1-2]

 

“The simplest bacteria or archaea are also incredibly complex structures, typically containing thousands of genes and complex metabolisms with intricate control mechanisms. It remains challenging to understand how something as seemingly simple as a single-celled organism arose. It is thought that the first cells, sometimes referred to as protocells, must have been much simpler than even the simplest modern prokaryote.” [Prebiotic, p.2]

 

 

 

Let’s get a visual on this ‘gulf’ between non-life and life, starting with ‘how much stuff’ is inside even the smallest of living/semi-living cells:

 

Here’s a chart of the number of ATOMS in the largest INORGANIC molecule (Packratite), the smallest virus, the smallest living cell (obligate), and the smallest free-living cell:

This chart is on the log scale which means each ‘layer’ is an order of magnitude higher than the previous one – e.g. 10 times greater.

 

Notice :

·         That our inorganic molecule has 376 atoms, and the smallest virus has a thousand times more atoms in it.

·         That the smallest cell considered alive, has 1 million TIMES more atoms inside it.

·         That the smallest free-living cell has over 7 million TIMES more atoms inside it.

 

For these tiny cells to have so many elements inside them, gives a good sense that they are certainly ‘complex’ in their makeup!

 

ATOMS inside these cells are obviously combined into MOLECULES. And their story is just as indicative of complexity as the other.

 

Here is a chart of those smallest living things (plus  E. coli as reference). The bars represent the relative sizes of the cells, with the organism’s name/type, and with the weight of that cell on the right [“fg” stands for “femtogram” =  10^(-15) grams. A dry grain of rice weighs about 20 million femtograms.]

 

The number inside the bars represents the average number of MOLECULES in that species’ cell.

So, the smallest living thing on the planet (that we know of) has 3.4 MILLION molecules in it.

 

We can even be amazed at the SCALE of these components/cells, when compared to cosmic phenomena. I selected only certain items for comparison—more could be done, with similar results:

The summary of this data offered by Claude-AI, highlights the scale differences:

 

“This logarithmic chart reveals the staggering abundance of life's molecular components compared to astronomical objects. The scale above spans from 10⁹ to 10⁴⁶ - that's 37 orders of magnitude!

 

“Key insights:

• All human cells on Earth combined (~3.7 x 10²³) are roughly comparable to the number of stars in the observable universe (10²⁴)

• There are more insects on Earth (~10¹⁹) than there are galaxies in the universe (10¹²) by a factor of 10 million

• A single human body contains ~40 trillion bacterial cells (10¹³) - about 100 times more bacteria than there are stars in the Milky Way

• A single teaspoon of seawater contains about a billion bacteria.

• Water molecules in living things outnumber stars in the universe by 10²² (10 thousand billion billion times)

• The entire observable universe contains roughly 2 trillion galaxies, each with billions to trillions of stars

 

“While the universe is vast in terms of space, life is extraordinarily rich in complexity and quantity at the molecular scale.

 

“This chart reveals that even though individual organisms are tiny, the collective molecular abundance of life on Earth rivals or exceeds the quantities we see at cosmic scales. A single human is a walking ecosystem containing more bacterial cells than stars in our galaxy!”

 

 

 

You should be able to get an intuitive sense of how COMPLEX (and maybe ‘cluttered’?) these simple life-forms are.

 

 

ACTIONS: It is in this area that the uniqueness of the cell stands out so sharply.

 

These molecules are not just ‘floating around’ inside some kind of pool inside the cell walls. They are in constant motion and constant activity, being driven by the ‘decisions’ by the cell. They are agents in an endless cycle of metabolic reactions that interface with other metabolic reactions, all monitored and regulated by the cell itself.

 

We will get to the interactions between them, in the step about ‘repeatedly ‘act on’ one another (i.e., metabolism), but let me give some data on HOW BUSY these little components are:

 

“Within cells, there are enzymes that perform millions of chemical reactions each second. Protein ‘motors’ make energy-storing molecules by spinning around thousands of times a minute. Sugar molecules fly by at 250 miles per hour, nearly double the speed of a Cessna 172 airplane at cruising speed. Every protein in the cell is hit by 10¹³ water molecules every second.” [Niko McCarty, Fast Biology, Asimov Press]

 

“… ATP synthase, a barrel-shaped protein, made from three subunits, that makes the energy storage molecules of the cell. ATP synthase does this by combining ADP with a free floating phosphate to form ATP. The barrel-shaped protein sits embedded in a membrane and performs this chemical reaction by harnessing the flow of protons down a concentration gradient. It spins around and around, each rotation yielding three molecules of ATP. Making ATP is, for these reasons, both a chemical and a mechanical process. … The scientists observed that ATP synthase spins around exactly 134 times each second, or 8,040 times each minute. That speed is significantly faster than the propeller on most piston airplanes, and about half the RPM of a Boeing 737 jet engine.” [Niko McCarty, Fast Biology, Asimov Press]

 

“We make use of one of our tricks of the trade which states that in E. coli a single molecule per cell (say our substrate) has an effective concentration of about 1nM (i.e. 10^-9 M). The rate of collisions is thus [math removed], i.e. they will meet within a second on average. This allows us to estimate that every substrate molecule collides with each and every protein in the cell on average about once per second. As a concrete example, think of a sugar molecule transported into the cell. Within a second it will have an opportunity to bump into all the different protein molecules in the cell.” [Cell Biology by the Numbers, p. 275, Milo/Phillips/Orme.] Note from above that there are 3,000,000 proteins in a single E. Coli cell.

 

“Another tiny bio-machine that has attracted a lot of attention is a sort of freight-delivery molecule called kinesin. It carries vital cargoes by walking along the tiny fibres which crisscross cells. It does this gingerly – one careful step at a time – to avoid being swept away by the incessant bombardment from the thermally agitated water molecules that saturate all living cells and move twice as fast as a jetliner. One foot stays anchored to the fibre and the other comes from behind and sets down ahead; then the process is repeated with the other foot. The anchor points are where the binding forces between the foot and the fibre are especially propitious: those sites are 8 nanometers apart, so each step is 16 nanometers in length. It’s unnerving to think that billions of these little kinesin wonders are creeping around inside you all the time. [Davies, Demon, p.57]

 

 

 

 

1A: REPEATEDLY ‘act on’ one another…

 

This is the amazing cellular process called ‘metabolism’—in which these millions of chemical reactions and processes run constantly, and produce outputs that are used as inputs in OTHER chemical reactions. These overlapping and intertwining processes work as a network, with control mechanisms and alternatives.

 

These ‘chains’ of chemical reactions are known as ‘pathways’, and there are a few that are considered ‘central’, because they produce both their OWN primary output, but also metabolites that FEED other pathways.

 

“While individual organic reactions and the synthesis of specific compounds were undoubtedly important for the origins of life, these must have become organized into connected networks which helped convert environmentally supplied compounds into the components of the network, which stored and processed information about the network, catalysed the network and helped maintain its components in close spatial proximity. …  “The network of reactions occurring within cells which affords the synthesis and breakdown of the materials life needs (e.g. amino acid and nucleotide building blocks), as well as the energy producing re-actions needed for general cell maintenance also matter. Cells carry out an incredible number of coordinated reactions in this manner. The biosynthetic pathways, which help interconvert the material composition of the cell as well as provide energy for cell function are collectively referred to as metabolism.” [Prebiotic, p. 47]

 

“The chemical reactions of metabolism are organized into specific pathways, which are typically (but not always) catalyzed by protein enzymes. This organization into pathways is crucial for allowing efficient capture and use of the energy provided from and required for different transformations…While each organism has its own particular set of metabolic reactions as a consequence of its evolutionary ancestry, there are some core pathways which are common to nearly all organisms, albeit with some modifications depending on the organism in questions. In this chapter, we will briefly survey some of these central prokaryotic metabolic pathways that provide precursor metabolites for other pathways.” [Prebiotic, p. 46]

 

The Primer on Prebiotic Chemistry that I have been quoting from lists these as the central pathways for Prokaryotes (archaea and bacteria);

 

·         Tricarbolic acid cycle (TCA, aka citric acid or Krebs cycle). It produces the ‘energy packet’ ATP, and provides intermediates for the lipid, amino acid, and nucleotide biosynthesis pathways.

·         Acetyl-CoA pathway. This produces Acetyl-CoA from CO2.

·         Glycolysis. Breaks down sugar, giving ATP , and supplies intermediates to other pathways.

·         Pentose phosphate pathway (PPP). This runs in parallel with glycolysis and shares some of the same intermediates. It is critical for providing the pentose phosphates need for DNA, RNA, and other cofactors.

 

Other pathways (needed for synthesis of other needed compounds):

·         Gluconeogenesis – opposite of glycolysis – rebuilds sugars.

·         Amino Acid biosynthesis. Uses intermediates from the TCA/Krebbs cycle to make amino acids.

·         Nucleotide biosynthesis. These are multiple pathways, constructing RNA and DNA nucleotides.

·         Phospholipid biosynthesis. Creates needed chains of lipid molecules.

 

Just to show you the complexity of these, here are THUMBNAILS of the schematics for them.

Just these images will give you a sense of how CONNECTED these things are – how they are constantly and REPEATEDLY ‘acting upon’ one another.

 

And this is just for prokaryotes as a group…

 

 

For the archaea sub-set of those, here is a glimpse of just one of the pathways, the central metabolic pathway, for one of the members:

Each one of the nodes in those maps/schematics represents more LEVELS OF DETAIL down (at least one).

 

[From the BRENDA enzymes site, at the MetaboMAPS sub-site for pathways:

   https://metabomaps.brenda-enzymes.org/ ]

[Also see the Protein Data Bank, with visualizations of proteins and seqs:

  https://www.rcsb.org/ ]

 

 

 

There is an on-line ‘master’ schematic of all known (or possible) pathways, for most known life forms, posted online, which can be populated with specifics by species, and interrogated by pathway:

[ https://www.kegg.jp/kegg/pathway.html   ]

 

 

Here is the master template from the site, with the lines representing pathways and the nodes representing compounds:

Just for shock value to show the ‘organic depth’ of life– (lol) – here is the master schematic with some of e. Coli’s pathways selected:

And here is the drill-down on the red-dotted area. When clicking on a node in the chart, it opens up a window describing the COMPOUND, and then there are links to all the REACTIONS it participates in…the entire diagram is like this, revealing the deeper and deeper levels of complexity (and sophistication) of the living cell:

This complexity is mind-boggling—especially at that scale/size!—and seems so out-of-place, compared to the levels of complexity ‘beneath it’ (i.e. inorganic materials), and even—in some real sense—beyond the complexity of the physical cosmos itself (as noted above).

 

 

More or less incomparable:

 

“Cells are amazing. Even to a non-biologist, they convey the impression of being very special objects with extraordinary capabilities. No one who has observed a leucocyte (a white blood cell) purposefully—one might even say single-mindedly—chasing after a bacterium in a blood smear would disagree. … What one witnesses there seems to transcend all our intuitions: A tiny speck of matter, invisible to the naked eye, so small that one hundred of them could be lined up across the top of a pin, is seemingly endowed with intention and agency. It's like watching a house cat chasing a mouse, or a cheetah chasing a gazelle on the African savanna, or indeed a man chasing down a kudu in the Kalahari.

 

“It does not lessen the amazement to conclude that this ability must arise somehow from the atomic complexity that lies within this wondrous speck of matter. For the complexity in which this behavior is instantiated is also far beyond ordinary experience. A cell consists of trillions of atoms, representing the complexity of a jumbo jet and more, packed into a space less than a millionth of the volume of a typical grain of sand. But unlike any jumbo jet, unlike any nano-tech, or indeed unlike even the most advanced human technology of any kind, this wondrous entity can replicate itself. Here is an "infinity machine" with seemingly magical powers…

 

“In terms of compressed complexity, cells are without peer in the material world, actualized or imagined…There is much more to discover about the cell, but even from our current limited knowledge of its depths it is clear that this tiny unit of compact, adaptive sophistication constitutes something like a third infinity. Where the cosmos feels infinitely large and the atomic realm infinitely small, the cell feels infinitely complex.”

[Denton, Miracle, p16]

 

And the more that researchers learn, the deeper the mysteries are, and the more ‘poorly understood’ phrases there are (which still amaze us in their sophistication):

 

“Only as the veil began to lift with the mid-century molecular biological revolution did science begin to glimpse the sophistication of these extraordinary pieces of matter. Subsequently, every decade of research has revealed further depths of complexity. The discovery of ever more intricate structures and systems with each increase in knowledge—including vastly complex DNA topologies and a vast and growing inventory of mini-RNA regulator molecules—tells us there is probably much more to uncover. What we glimpse now may be only a tiny fraction of what remains to be discovered.

[Denton, Miracle, p16]

 

“As Erica Hayden confessed in the journal Nature, “As sequencing and other new technologies spew forth data,” the complexity unearthed by cell biology “has seemed to grow by orders of magnitude. Delving into it has been like zooming into a Mandelbrot set… that reveals ever more intricate patterns as one peers closer at its boundary.””

[Denton, Miracle, p16]

 

 

 

 

1B: Maintain a shared ‘clock’…

 

In unicellular organisms, the internal sub-parts have to be synchronized for the intermediates to be taken up into the next pathway. The synchronization task is critical, and of course, it is much worse for multicellular life…

 

The mechanisms used in timing are amazing, having to overcome both randomness and unexpected change…

 

And—as with most ‘seemingly intelligent cellular processes’—they are ‘poorly understood’ … LOL

 

“The correct timing of molecular and cellular events is critical for embryo development, cell/tissue homeostasis, and to functions in all organisms throughout their whole lives. Thus, it plays a major role in biology. Despite this obvious key role of timing in all biological processes, we do not know exactly how cells and organisms measure time and how they translate the information on time flow to the correct regulation of molecular processes… Cells and organisms also measure time flow, react to time passing, and may modify processes using time through accelerating, delaying, or postponing certain reactions … Biochemical processes must progress using time with appropriate timing, and the correct sequence of events is strictly controlled using time to ensure their full coordination and purposefulness for the cell, tissue, and organism’s life. Checkpoint mechanisms monitor if the necessary processes have been completed before starting new ones. Thus, the precise timely coordination between molecular events/reactions/pathways and their specific regulation in different conditions allows for the harmonious functioning of cells, tissues, organs, and whole organisms .. The review article by Yool Lee and Jonathan P.Wisor discusses how circadian clocks reciprocally interact with other signaling and metabolic factors to coordinate daily rhythms. Numerous cellular and animal models demonstrate the presence of functional circadian oscillators at multiple levels, ranging from individual cells, like neurons or fibroblasts, to the brain and peripheral organs. These oscillators are tightly coupled to the timely modulation of cellular and bodily responses to physiological and metabolic cues.”

[Kubiak, J.Z.; Kloc, M. “How the Timing of Biological Processes Is Controlled and Modified at the Molecular and Cellular Level” 2.0. Biology 2024, 13, 170.]

 

“Many developmental processes depend on precise temporal control of gene expression..  This timing mechanism acts across a cell division that occurs in the neuroblast lineage and is influenced by the asymmetry of the division. Finally, we show that positive feedback of receptor expression through the canonical Wnt pathway enhances temporal precision. We conclude that robust cell-intrinsic timing can be achieved by combining regulation and feedback of the timekeeper gene…. 

To measure time, biological clocks generally utilize a component that increases or decreases in activity or abundance (a timer) or cycles through a high and low state (an oscillator) and triggers a response when a specific threshold is crossed (--). …. In clocks that act across multiple cells, robustness can be increased through averaging, synchronization through intercellular communication (--) or entrainment using external signals (--). The cell intrinsic mechanisms that control the timekeeping mechanism itself are, however, still poorly understood… [Journal Editor's evaluation: This paper (above) deals with an important unsolved problem in developmental biology: how cells execute their dynamics at the right time. The study combines compelling quantitative single-cell and single-transcript experiments with genetic perturbations and computational modelling and provides important insights into how the timing of transcription is regulated.]

[Erik S Schild, Shivam Gupta, Clément Dubois, Euclides E Fernandes Póvoa, Marie-Anne Félix, Andrew Mugler, Hendrik C Korswagen (2023) “Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor”, eLife 2023;12:e82675]

 

   

“Timing is essential for many cellular processes, from cellular responses to external stimuli to the cell cycle and circadian clocks. Many of these processes are based on gene expression. For example, an activated gene may be required to reach in a precise time a threshold level of expression that triggers a specific downstream process. However, gene expression is subject to stochastic fluctuations, naturally inducing an uncertainty in this threshold-crossing time with potential consequences on biological functions and phenotypes. Here, we consider such timing fluctuations, and we ask how they can be controlled. Our analytical estimates and simulations show that, for an induced gene, timing variability is minimal if the threshold level of expression is approximately half of the steady-state level. Timing fluctuations can be reduced by increasing the transcription rate, while they are insensitive to the translation rate. In presence of self-regulatory strategies, we show that self-repression reduces timing noise for threshold levels that have to be reached quickly, while self-activation is optimal at long times.”

[“Stochastic timing in gene expression for simple regulatory strategies”. Alma Dal Co1, Marco Cosentino Lagomarsino2,3,4, Michele Caselle1 and Matteo Osella1, Nucleic Acids Research, 2017, Vol. 45, No. 3 1069–1078]

 

 

“Circadian rhythms are observed in a wide variety of biological, physiological and metabolic processes in most organisms. These rhythmic cycles are governed by an endogenous circadian clock. Thus, a crucial function of the endogenous circadian system would be to anticipate and adapt to environmental changes in light, temperature, food and even mate availability, and organize behavior and physiology to these changing situations. In addition, the circadian system plays a regulatory role by the temporal coordination of physiological, cellular and molecular processes such that synergistic processes are timed to coincide, whereas processes that are conflicting are temporally separated. There is increasing evidence that a smoothly running endogenous clock is crucial for energy balance in organisms from cyanobacteria to mammals [--]. … The rhythm can also be entrained by changes in timing of food and temperature (although the period of rhythm can be stable over a wide range of temperature—i.e., it can be temperature compensated) [--]. The importance of the circadian clock for organismal homeostasis was demonstrated by loss of sleep/wake cycles and metabolic defects following targeted disruption of core clock genes in mice [--]. Additional roles of clocks in basic cellular pathways have also been elucidated such as regulation of nutrient and energy balance, cell cycle, DNA-damage repair and xenobiotic detoxification [---]. In view of these data, it should not come as a surprise that disruption of circadian rhythms would increase vulnerability to stressors, accelerate aging and could lead to various pathologies including cancer …. Circadian rhythms have been described in both prokaryotes and eukaryotes, and many molecular features associated with the circadian clock are evolutionarily conserved.”

[“Nature’s Timepiece—Molecular Coordination of Metabolism and Its Impact on Aging”. Andrea Bednářová, Dalibor Kodrík and Natraj Krishnan, Int. J. Mol. Sci. 2013, 14, 3026-3049].

 

"The molecular clock network consists of transcriptional and translational feedback loops where core clock genes are transcribed and these translational products inhibit their own transcription. These timed transcriptional and translational feedback processes generate the molecular rhythms, which eventually translate to the circadian rhythms observed in most organisms. The basic organization of the circadian clock has a hierarchy—with every cell in the organism having an autonomous clock, and different cells and tissues are synchronized to oscillate with the same phase. This orchestration occurs via the “central” or “master” clock, which is entrained by input from zeitgebers. Genetic analyses have revealed numerous clock genes in different species and most studies to date have focused on understanding the molecular mechanisms of the rhythms generated by these core clock genes.”

[“Nature’s Timepiece—Molecular Coordination of Metabolism and Its Impact on Aging”. Andrea Bednářová, Dalibor Kodrík and Natraj Krishnan, Int. J. Mol. Sci. 2013, 14, 3026-3049].

 

 

“The inherent probabilistic nature of biochemical reactions and low copy numbers of  molecules involved result in significant random fluctuations (noise) in protein levels inside isogenic cells inhabiting the same environment (--). Although the origins of stochastic gene expression have been extensively studied across organisms, the impacts of the noisy expression of key regulatory proteins on the timing of intracellular events is underappreciated (--). Identifying regulatory motifs that buffer randomness in the timing of intracellular events has important consequences for disparate cellular processes, such as apoptosis, cell-cycle control, cell differentiation, and sporulation, where precision required for proper system functioning depends on regulatory molecules reaching critical threshold levels at the right time… In another example, proper timing of yeast cell division is ensured by the precise expression of a regulatory protein, Cln, up to a critical threshold level (--). Despite these significant impacts, how cells maintain precision in event timing despite noisy gene expression remains poorly understood. … In summary, our study uncovers mechanisms for generating precision in the timing of cellular events given the unavoidable constraints of stochastic gene expression and dilution from cellular growth.”

[“Optimum Threshold Minimizes Noise in Timing of Intracellular Events”. Kannoly et al., iScience 23,, 101186, June 26, 2020 ]

 

 

Here is a table/list of the biological clocks in use by cells – notice the complexity that this implies:

From “Keeping track of time: The fundamentals of cellular clocks”, Colin R. Gliech and Andrew J. Holland, J. Cell Biol. 2020 Vol. 219 No. 11, page3]

 

 

 

…………………..

Timing is important to spacing accuracy, as seen in size-control for example:

 

“Growth of a cell and its subsequent division into daughters is a fundamental aspect of all cellular living systems. During these processes, how do individual cells correct size aberrations so that they do not grow abnormally large or small? How do cells ensure that the concentration of essential gene products are maintained at desired levels, in spite of dynamic/stochastic changes in cell size during growth and division? Both these questions have fascinated researchers for over a century. We review how advances in single-cell technologies and measurements are providing unique insights into these questions across organisms from prokaryotes to human cells. More specifically, diverse strategies based on timing of cell-cycle events, regulating growth, and number of daughters are employed to maintain cell size homeostasis. ….”

[“Cell size control and gene expression homeostasis in single-cells”. Cesar A. Vargas–Garcia1, Khem Raj Ghusinga, and Abhyudai Singh. Curr Opin Syst Biol. 2018 April ; 8: 109–116]

 

 

“All living systems display remarkable spatial and temporal precision, despite operating in intrinsically fluctuating environments. It is even more surprising given that biological phenomena are regulated by multiple chemical reactions that are also random. Although the underlying molecular mechanisms of surprisingly high precision in biology remain not well understood, a novel theoretical picture that relies on the coupling of relevant stochastic processes has recently been proposed and applied to explain different phenomena … In this review, we provided novel microscopic insights into how biological systems achieve precise control over spatial and temporal processes despite the inherent randomness of molecular interactions. By examining bacterial cell-size regulation and the timing of cell lysis in l bacteriophage, we demonstrate that cells can harness stochastic processes to ensure reliable outcomes. In bacterial cells, balanced growth and division rates lead to stable size distributions, whereas, in l phage, holin protein accumulation triggers timely lysis, achieving effective threshold-like behavior. These studies highlight universal mechanisms by which cells adapt precision strategies in size and timing, advancing our understanding of cellular regulation.”

[“Microscopic origin of the spatial and temporal precision in biological systems”. Anupam Mondal and Anatoly B. Kolomeisky. Biophysical Reports 5, 100197, March 12, 2025

 

Although we are mostly focused on unicellular organisms here, most of it applies to multi-cellular life also:

 

“Multi-cellularity would be impossible without  communication, as the existence of the multicellular state hinges upon making sure that the cells’ decisions are perfectly synchronized, and that cells do  not act independently of others. “  [Adami, p. 509]

 

“Genetic programs did not begin with animal cells. Indeed, all prokaryotes and even viruses have genetic programs. But animals stand apart for their genetic programs because most of them—the ones we are interested in here are associated with the emergence of different cells—run sequentially, one after another, and in parallel in the different cells that make up the organism. As I have said, the core of these programs is the sequence of events created by the chemistry inside the cell, but then something needs to coordinate these across cell populations and, moreover, across different cell populations within the organism. We do not yet know how this happens, but we do know that the cell is responsible for it and that the signaling kit that we can see for the first time in sponges has much to do with it. Once again, genes and their chemical actions are under the control of cells.”  [Arias, Master, p. 115]

 

“From this perspective, the genes in a cell are functionally similar to the different agencies in a self-maintaining ecosystem. The reactions they trigger must be coordinated or mutually adapted so that the one produces what the others consume, and the system as a whole remains in balance—while being quick to adjust to fluctuations in the concentrations of the different molecular "species," or to the entry of food molecules that must be consumed or toxins that must be neutralized. Thus, for a cell to survive, its genes must efficiently cooperate, forming a synergetic whole where everything needed by one process is produced by one or more other processes, and vice versa. Note that these processes generally include reactions that transport resources into the cell and waste out of the cell. Therefore, the system is not closed in the thermodynamic sense, only in the organizational sense.” [Purpose, p. 95]

 

…………………………………………………………………………………………….

 

 

1C. Respond to internal threats (e.g. DNA and cellular repair mechanisms)…

 

We noted above that the cell exerts many control forces over metabolic processes (esp. relating to timing).

 

The complexity of the cell and its systems present a large ‘attack surface’ for deleterious impacts. The management system of the cell and the information center (DNA) of the cell, are BOTH fallible, and if compromised enough, can trigger the failure of the cell.

 

These management capabilities are therefore essential and must be protected (and repaired when damaged) at all costs.

 

Everything breaks, and everything in the cell requires monitoring and repairing and --sometimes—destroying and disposing.

 

Barbara McClintock received the Nobel Prize in 1983, for her work in  genetic change. She had this to say at the award ceremony:

 

“The conclusion seems inescapable that cells are able to sense the presence in their nuclei of ruptured ends of chromosomes and then to activate a mechanism that will bring together and then unite these ends, one with another ... The ability of a cell to sense these broken ends, to direct them toward each other, and then to unite them so that the union of the two DNA strands is correctly oriented, is a particularly revealing example of the sensitivity of cells to all that is going on within them... … We know nothing, however, about how the cell senses danger and instigates responses to it that often are truly remarkable.” [given in Davies, Demon, pp. 127-128]

 

 

The cell does this through diverse and complex repair mechanisms, that vary by organism.

 

 

The events of damage fall into three categories:

1.      Genetic damage – DNA focused, damage to the information center

2.      Phenotypic mutations –

a.       errors in creation of mRNA (transcription) and then

b.      errors in making polypeptides (translation), and then

c.       errors in making working proteins (folding)

3.      Non-genetic cell elements (membrane, mitochondria, etc)

 

·         The cell concentrates on #1, Genetic damage , since the DNA contains much of the information needed for operations and it is the only element that is sure to be passed down to the next generation.

·         Errors in #2, Phenotypic mutations , are less severe (but much more common), since they do NOT typically pass down to the next generation, they rapidly degrade, and they can easily/quickly be replaced.

·         Some damages in #3 can be fatal, so they have mechanisms to repair them too.

 

 

 

Complex organisms could not function without these repair functions – the error rates are too high:

 

“With a natural error rate in DNA copying, complex organisms could not function. It would produce hundreds of thousands of errors that would destroy the organism. Furthermore, the error-correcting process needs to be able to identify and target the errors. The error-correcting process cannot function without this ability. The double helix structure enables the fitness of two nucleotides to be detected. Without this, an error could not be detected. But the double helix, in itself, does not explain how the corrections happen.  … When cells divide, DNA is replicated with amazing accuracy. But this does not occur by accident. It occurs through an equally amazing cellular process. DNA does not achieve this by itself. On its own, there would be hundreds of thousands of mistakes every time the genome is copied. Accurate replication can only be performed in a cell with all the cellular error-correcting machinery to reduce an error rate of 1 in 10,000 to just 1 in 10 billion. The correcting process involves an army of unique proteins olymeriz by the cell. Furthermore, this provides a way for the cell to alter the DNA, because it is a targeted process.” [Living Systems, pp. 16ff]

 

“What if they could actively manipulate their own genomes? Actually, it is clear that they do. Sexual reproduction involves several slicing-and-dicing genomic reconfigurations, some random, some supervised. Many intermingling methods are out there, each of which involves cells shuffling their own DNA in a carefully arranged manner. And sex isn’t the only example. Correcting the errors that occur during DNA replication requires another set of genomic management operations. Most of the primary damage to DNA, for example by radiation or thermal disruption, never makes it to the daughter cells because it is repaired first. Human DNA would suffer devastating mutational damage, estimated at an overall 1 per cent copying error rate per generation, without all the in-house, high-tech proofreading, editing and error correcting which reduces the net mutation rate to an incredible one in 10 billion. So cells are able to monitor and actively edit their own genomes to a high degree of fidelity in an attempt to maintain the status quo.” [Davies, Demon, pp. 127f]

 

Because of the all-important DNA, the cell devotes a ton of resources to it!

 

“Evolution of life is fully based on digital information transmission processes —across generations via genome replication and from the genome to the effector molecules (RNA and proteins). No information transmission channel is error-free, as first formally asserted by Claude Shannon, who founded information theory by connecting information transmission with the laws of thermodynamics. As noted in Chapter 2, the fidelity of genome replication cannot be lower than a certain minimum; conversely, the mutation rate cannot exceed a certain threshold, to avoid the mutational meltdown of the population. .. Selection for a sufficient fidelity of replication (and more generally all processes of information transmission) is one of the central aspects in all evolution. This is immediately obvious from the enormous diversity, complexity, and multilayer organization of repair systems that exist in all cellular life forms (---). In prokaryotes, up to 10% of the coding capacity of the genomes may be dedicated to repair system components that act at all stages of DNA replication and also eliminate various mutational lesions that occur outside the replication process.” [Koonin, pp. 274-276]

 

 

The repair mechanisms for DNA are very complex, and must have been present in the first cells, since – without their repair work—the replication error rate would have doomed the downstream progeny.

 

“Even when selection and adaptation clearly are involved, the manifestation of these factors of evolution often (possibly, most of the time) is quite different from the (neo) Darwinian idea of “improvement.” Often adaptations have to do with maintaining the integrity of cellular organization, preventing malfunction, and performing damage control. In a sense, this is a trivial statement of fact, considering the expanse and complexity of the molecular machinery that is dedicated to quality control of each of the major information transfer processes: Systems of DNA repair and protein degradation, and molecular chaperones are all cases in point. Moreover, much, if not most, of the evolution of protein-coding genes appears to be driven by selection for robustness to misfolding. In multicellular organisms, the importance of the selection for prevention of malfunction is apparent at the level of cell and tissue interactions, as illustrated by the highly complex systems of programmed cell death. In retrospect, all these findings may appear quite intuitive, considering how advanced, complex, and, in a variety of ways, optimized cells and even individual protein or RNA molecules are. Once these complex systems are in place—and evolutionary reconstructions clearly show that they have been in place for most of the history of life, that is, more than 3.5 billion years—quality control and damage prevention indeed become the bulk of the “work” of evolution, the importance of occasional new adaptations notwithstanding. This realization places an enormous burden on the early, precellular stages of evolution when change must have been rapid and the roles of positive selection along with constructive neutral evolution must have been much greater than they were during the subsequent 3.5 billion years of evolution. In a sense, almost everything “really interesting” in the evolution of life occurred during its relatively brief, earliest stages antedating the “crystallization” of the basic cellular organization. Certainly, major exceptions exist, such as the emergence of eukaryotic cells or multicellular eukaryotic organisms, but there is no doubt that most of the fundamental evolutionary innovations are crammed into the earliest 5% of the history of life.” [Koonin, pp. 401-402]

 

 

 

There are multiple types of damage that can occur, but these two diagrams will show both the typical sources of mutation, and the complexity of a few of the repair mechanisms:

There are more repair mechanisms than in the below image, but this diagram illustrates the pathway complexity (but only at a high level!) of a few of the repair mechanisms:

These are fast, dedicated pathways – the Mismatch Repair (MMR) above in the left column uses between 200 and 300 total molecules (typical repair), involving between 100,000 and 150,000 atoms in those molecules… for this one specific function.

 

Replication fidelity is fairly small, but the repair mechanisms powerfully reduce errors:

·         DNA polymerase alone:                     ~10⁻⁴ to 10⁻⁵ (1 error per 10,000-100,000 bases)

·         + 3’ to 5’ exonuclease proofreading: ~10⁻⁶ to 10⁻⁷ (100-1,000x improvement)

·         Mismatch repair (MMR):                  ~10⁻⁹ to 10⁻¹⁰ (another 100-1,000x improvement)

 

The error rates of phenotype mutations go UP as the process gets farther away from the DNA:

 

“The error rate of transcription is much higher than that of replication, and the error rate of translation is much higher yet (see Figure 9-4). Although the experimental measurements of the amino acid misincorporation rate during translation are scarce and limited to a few model systems, it is clear that the fidelity of translation is almost shockingly low. Indeed, the rate of non-cognate amino acid incorporation is 10^(-4) to 10^(-5)—interestingly, close to the replication error rate in RNA viruses. Thus, about 20% of the protein molecules synthesized in any cell contain at least one wrong amino acid (---). The consequences of errors of transcription and translation, sometimes aptly called phenotypic mutations, obviously are less dramatic than the consequences of genetic mutations, for the very reason that phenotypic mutations are generally not inherited (notable exceptions exist, such as reverse transcription followed by the incorporation of a DNA copy of a mistranscribed RNA into the genome, ---). Given the relatively short lifetime of any RNA or protein molecule, no phenotypic mutation can have a major fitness effect on its own, so it is not surprising that much greater error rates are tolerated for phenotypic mutations than for genetic mutations. However, it is equally obvious that excessively high rates of phenotypic mutation are incompatible with life. Thus, as is the case with DNA repair systems, multiple mechanisms for keeping transcription and translation errors in check certainly exist. Proofreading activity of DNA-dependent RNA polymerases has been detected and shown to decrease the error rate by orders of magnitude (---). Moreover, still poorly characterized processes of post-transcriptional repair of methylation damage in RNA have been discovered as well (---). Probably the best understood of the mechanisms that control the rate of phenotypic mutations is proofreading by aaRS, in which aminoacyl-tRNAs charged with non-cognate amino acids are hydrolyzed and recycled (---). The aaRS proofreading is complemented by the downstream ribosomal proofreading, in which the ribosome rejects non-cognate tRNAs (---). However, a large increase of the translation accuracy seems to clash with the requirement of a high rate of protein production. A substantially increased translation fidelity can be readily achieved by mutating specific positions in rRNA or ribosomal proteins, but these mutations are deleterious, apparently, because of slow translation (--). “ [Koonin, pp. 277ff, and diagram below.]

The most common type of error is in the complex protein folding step—where the final shape of the polypeptide is important in becoming a useful protein.

 

From Koonin’s explanation  [Koonin, 277-279]:

 

“The principal deleterious effect of mistranslation is thought to be protein misfolding (---),  although amino acid misincorporation corporation at catalytic sites certainly could be an additional factor. … Regardless, although protein folding is not usually viewed as an information-transmission process, this is what it actually is. Indeed, folding involves the flow of information from the one-dimensional amino acid sequence to the three-dimensional protein structure. Exactly the same applies to structural RNAs. The rate of misfolding is hard to determine experimentally, and this has not been done for large sets of proteins or RNAs. If the trend of error rates depicted in Figure 9-4—the farther from the genome, the less accurate an information transmission step is—is any indication, the error rate of folding is expected to be even greater than the error rate of translation. This prediction also stands to reason, given the enormous complexity of the folding process and the vast number of (mis)folding pathways that are, in principle, available to a folding protein or RNA molecule (---). Given the high complexity of the folding landscape, the seminal discovery (made originally by Christian Anfinsen and subsequently confirmed in numerous experiments) that proteins can spontaneously fold into the native conformation came as a considerable surprise.

 

“Almost 50 years after Anfinsen’s discovery, it remains a matter of debate whether spontaneously folding proteins find the global or a local free energy minimum. What has become clear is that only small proteins fold spontaneously; the majority of proteins require special molecular devices, namely other proteins known as chaperones, to fold into the native structure. Chaperones function in a remarkable manner: The chaperone molecules form a “cage” (known also as the Anfinsen cage) that isolates the folding protein from the cytoplasm and partially unfolds it, thus facilitating the search for the native conformation (---). Most of the chaperones are abundant, highly conserved, high-status proteins. Originally, some of the chaperones were discovered as “heat shock proteins;” that is, proteins that are strongly upregulated at elevated temperature (and, as shown later, other stress conditions) and counteract protein misfolding, which is enhanced by the stress (---). Although not as well characterized, protein chaperones mediate RNA folding as well (---). On the whole, the control over protein (and probably RNA) folding undoubtedly is a major function in all cells.

 

“Beyond the chaperone-type devices, all cells dedicate a versatile repertoire of molecular machines to controlled degradation of proteins, particularly misfolded ones, and RNA. Similarly to molecular chaperones, these machines— the proteasome, in the case of proteins and the exosome (degradosome in bacteria), in the case of RNA—are ubiquitous in the three domains of life, highly abundant in most cells, and subject to regulation under stress (---). Furthermore, these machines, along with additional back-up systems of regulated proteolysis, are major intracellular consumers of energy (ATP). Bacteria additionally possess a highly conserved system of the so-called trans-translation that releases stalled ribosomes from aberrant mRNAs on which translation fails to terminate properly and targets such mRNAs and their (also aberrant) protein products for degradation (---).”

 

 

Beyond these gene-based issues, we have repair mechanisms for the other parts of a cell:

 

1.       Organelle-Level Repair

·         1.1 Mitochondrial Quality Control (eukaryotes only)

o    Mitochondrial DNA repair

o    Mitochondrial unfolded protein response

o    Fusion and fission dynamics

o    Mitophagy (selective autophagy)

·         1.2 Other Organelle Maintenance

o    ER-phagy (ER turnover)

o    Pexophagy (peroxisome turnover)

o    Lysosomal repair

2.       Bulk Degradation and Recycling

·         2.1 Autophagy (eukaryotes only, although maybe broader)

o    Macroautophagy

o    Microautophagy

o    Chaperone-mediated autophagy

o    Selective autophagy (mitophagy, pexophagy, etc.)

3.       Membrane Repair

·         Plasma membrane repair

·         Organelle membrane repair

·         Lipid remodeling and replacement

4.       Oxidative Damage Response

·         ROS neutralization (antioxidant enzymes)

·         Lipid peroxidation repair

·         Protein oxidation reversal

 

 

 

 

 

1D: Reproduce (when it senses that conditions are right for that)….

 

At a simplistic level, cells reproduce by making ‘two cells within one cell enclosure’ and then splitting this in half – with two identical cells, now separated.

 

Literally, everything inside the cell is DUPLICATED and/or elongated. The two sets of things move away from each other (in the elongated cell envelope) and then the cell is cut in half.

 

You have probably seen diagrams of this in high-school biology class, something like this:

It is called ‘binary fission’ (or in some cases, ‘mitosis’). It is a super complex operation, but can occur in prokaryotes every 10-30 minutes, and in humans, we have 25 MILLION cell divisions PER SECOND.

 

We know very little about how this is controlled, orchestrated, or even initiated – at the agent level. So, Arias, [Master, pp. 79ff] on eukaryotes:

 

“There is much we still don’t know about mitosis, particularly about the control and precise engineering of the spindle, centrioles, and chromosomes. But we can say that the answer to many of these questions cannot lie in the genes. Throughout the process of mitosis, genes remain inert, passive molecular structures. The chromosomes, on which genes reside, are copied and transported but have very limited involvement in what’s happening. Instead, it’s the organelles within the parent cell that sense space, balance forces, partition, and move chromosomes around. For example, we know that the timing of mitosis is not decided by one particular gene or even a collection of genes. Whether a cell divides or not relies on the assessment of many of its features: its volume, composition, stiffness, availability of nutrients, and signals from its neighbors. None of these can be directly linked to genes, though they will have an impact on the activity of the genome by determining the expression of certain genes whose products might be needed for a particular event—but the cell will decide what happens. “

 

“We are starting to learn how the cell does this; for the moment, however, we only have glimpses of the process. For example, a protein called mTOR plays a central role in gathering the information outlined above, determining when a cell will divide by controlling its growth. Found in all cells in the body, mTOR senses the cell’s health and available nutrients and, based on this information, decides whether it should make more nutrients, divide, or die. In a situation of stress, mTOR is able to read the state of the cell integrating many variables, measure them against the available nutrients, and, if possible, promote biosynthetic metabolism and growth. We still do not understand how it makes the decision.”

 

“In one dramatic instance, mTOR controls a process called autophagy, meaning self-devouring, in which, when stressed or running out of resources, a cell turns on itself and recycles its proteins and organelles, usually damaged ones, as a source of energy to stay alive. mTOR is a gatekeeper of autophagy. Usually it suppresses this process, favoring less dramatic ways to create mass and power, but if it assesses that there is not enough metabolic substrate for this, it will be switched off, allowing autophagy to proceed as an emergency system. This is an example of a vital activity that happens far from the realm of genes. Of course, mTOR is encoded by a gene, but this gene only provides the instructions for assembling the protein. It is mTOR that does the heavy lifting that keeps the cell alive. The protein’s function is determined not by the activity of the gene but, as with any sensor, by the protein’s interactions with other proteins and the wider chemical environment.”

 

And—in keeping with the data mentioned (profusely…sigh) above, this process is monitored CLOSELY, and even PAUSED if problems are sensed:

 

“Complex cells with a nucleus (eukaryotes) display a tightly controlled multistage cell division cycle. Each stage involves intricate processes such as cell growth, DNA replication, and accurate transmission of genome copies to daughter cells. Elaborate biochemical reactions regulate passage from one stage to the next. On top of the stage-to-stage control circuitry, a self-monitoring system makes sure everything comes out right. If the different biochemical and biomechanical processes fall out of sync, or if there is either a mistake or damage, sensory molecules detect the problem. They activate a checkpoint to hold up the entire cycle until everything has been set right for renewed progress. Cells set distinct checkpoint systems for growth and division.” [Shapiro, p. 198]

 

 

1E: Respond to External events (especially threats) as a unit, and …

 

This is one of fundamental characteristics of life – and ONLY of life and ALL of  LIFE.

 

“Moreover, modern organisms react to environmental signals and changes—this reactivity is one of the hallmarks of life, and importantly, the ability to learn how to react to such signals also requires explanation in order to fully solve the origin of life puzzle.” [Prebiotic, p. 41]

 

“All living cells sense and respond to changes in external or internal conditions. Without that cognitive capacity, they could not obtain nutrition essential for growth, survive inevitable ecological changes, or correct accidents in the complex processes of reproduction. Wherever examined, even the smallest living cells (prokaryotes) display sophisticated regulatory networks establishing appropriate adaptations to stress conditions that maximize the probability of survival. Supposedly “simple” prokaryotic organisms also display remarkable capabilities for intercellular signaling and multicellular coordination. These observations indicate that all living cells are cognitive.” [Shapiro, p. 928]

 

Bacteria, for example, have the ability to sense these external factors—through their cell wall—and take actions based on them. Here is a list of such sensors and what they do:

 

NUTRIENTS (Attractants)		Examples	Cellular Response
	Amino acids	Serine, aspartate	Smooth swimming toward source; continued flagellar rotation
	Sugars	Glucose, galactose, ribose, maltose	Smooth swimming toward source; uptake system activation
	Dipeptides	Various dipeptides	Smooth swimming toward source
	Oxygen	O₂	Aerotaxis toward optimal O₂ levels
TOXINS/REPELLENTS		Examples	Cellular Response
	Heavy metals	Nickel (Ni²⁺), cobalt (Co²⁺)	Tumbling/direction change (away from source)
	Weak acids	Various organic acids	Tumbling/direction change (away from source)
	Toxic compounds	Leucine, indole	Tumbling/direction change (away from source)
PHYSICAL PARAMETERS		Examples	Cellular Response
	pH changes	Acidic/alkaline conditions	Gene expression changes; stress response proteins; motility adjustments
	Osmolarity	High/low salt concentration	Porin expression regulation; compatible solute synthesis
	Temperature	Heat/cold stress	Heat shock proteins; cold shock proteins; membrane fluidity changes
QUORUM SENSING		Examples	Cellular Response
	Population density signals (Gram-negative)	Acyl-homoserine lactones (AHLs)	Biofilm formation; virulence factor production; bioluminescence
	Population density signals (Gram-positive)	Oligopeptides	Biofilm formation; competence; sporulation; virulence
CELL DENSITY / CONTACT		Examples	Cellular Response
	Cell-to-cell contact	Physical proximity	Conjugation; biofilm maturation; coordinated behavior

 

 

Different species can also sense other factors, which they respond to:

 

“Bacteria turn out to be highly versatile when it comes to guiding their swimming motility [---]. Among the 5 E. coli MCP receptors is one that senses oxygen and guides “aerotaxis” to more oxygenated zones of the growth medium. In addition to chemotaxis and aerotaxis, some bacteria like M. magnetotacticum have receptors called “magnetosomes” that sense the Earth’s magnetic field. Such sensing enables “magnetotaxis,” which effectively allows aquatic cells to move either up or down in a controlled manner [--]. Many bacteria also have light receptors that guide “phototaxis” (movement toward light), “photophobia” (movement away from light), or more complex behaviors in the illuminated environment [--].”  [Shapiro, p. 934].

 

In some cases, they recognize incoming DNA sequences as being ‘not self’!

 

“Bacteria have at least three different systems [one of which is CRISPR-Cas system] for recognizing incoming DNA and discriminating between it and their own genomic molecules..” [Shapiro, p. 950]

 

[More on this in the next section on ‘social issues’…]

 

 

1F:  Occasionally MODIFY THEMSELVES as needed to fulfill the requirements above…

 

This statement would have been blasphemous up until recently, since the cell was believed to be passive in its genetic future. Change came from mutations, and mutations were random—the cell was only the recipient of change, and not the instrument of change.

 

That old position (the Central Dogma) is very far from the consensus view today, and runs counter to the mass of data gathered in the last couple of decades.

 

“A key proposition of the Central Dogma is that cells cannot alter DNA in a directed way. Furthermore, there is assumed to be no facility for such alteration. However, this proposition is not based on experimental evidence, and there is a growing body of evidence that it is false. It is based on the idea that the transcription process from DNA to protein cannot work backwards. But the cell does not need to do this to alter the genome. In one sense, it merely needs to allow changes to occur, as it can, for example, by varying the error correction process, or by large-scale chromosome and genome rearrangements, and then choose between the variants.……Cells can influence the DNA, not through back-translation from protein to DNA, but by using the processes that enable the DNA to be corrected, and precisely this mechanism operates in the immune system. Thus, DNA is regulated by the system, and it can also be altered by the organism.……Yet, by reverse transcription it becomes possible to transfer sequences, including whole domains corresponding to functional parts of proteins, from one part of the genome to another. We know that this has happened during evolution.” [Living Systems, p. 22]

 

“Organisms can achieve genome reorganisation in several ways, not least by splicing and translocating sections of DNA. Indeed, this process has played a significant part in adaptive evolutionary change. It pulls apart the Central Dogma. The genome can be reorganized. Yet such was the hold of the Central Dogma that the evidential basis for this could not be published in standard scientific journals for many years. The evidential basis is now substantial, beginning notably with Barbara McClintock’s work in the 1930s, 1940s and 1950s. McClintock showed genome reorganisation in corn (maize), where large domains are moved from one region of the genome to another in response to environmental stress, and even from one chromosome to another. Eventually, when it became clear that many others had found the same process in other organisms, McClintock received the Nobel Prize in 1983. She wrote: “In the future attention undoubtedly will be centered on the genome, and with greater appreciation of its significance as a highly sensitive organ of the cell, monitoring genomic activities and correcting common errors, sensing the unusual and unexpected events, and responding to them, often by restructuring the genome.” (our emphasis).” [Living Systems, p. 23]

 

McClintock faced ‘central dogmatic’ skepticism (smile), but her experience and her statements at the Nobel prize ceremony were incontestable [from Davies, Demon, pp. 127-129]:

 

“But now we encounter a fascinating question: can cells actively edit their genomes to change the status quo? Decades before the work of Cairns and Rosenberg this question was investigated in a series of remarkable experiments by the distinguished botanist and cell biologist Barbara McClintock. Starting in her student days in the 1920s, she experimented with maize plants and established many of the basic properties of chromosome structure and organization we know today, for which she subsequently received a Nobel Prize in Physiology or Medicine — the first woman to win the prize unshared in that category. With the help of a basic microscope, McClintock looked to see what happened to the chromosomes of the maize plants when they were exposed to X-rays. What she reported caused such a ballyhoo and attracted so much scepticism that in 1953 she felt moved to stop publishing her data. What was uncontentious were her observations that chromosomes break into fragments when irradiated. But the big surprise was the fact that the pieces could rejoin again, often in novel arrangements. Humpty-dumpty could be reassembled in a baroque sort of way. Chromosome reorganization writ large might seem lethal, and it often was. But it was not always so: in some cases, the mutant plants went on to replicate their grossly modified genomes. Crucially, McClintock found that the large-scale mutations were far from random; it appeared that the maize cells had a contingency plan for the day their genomes were smashed. Even more amazingly, if the plants were stressed, for example by infection or mechanical damage, spontaneous chromosome breakage could occur without the benefit of X-ray disruption; the broken ends were rejoined after the chromosome replicated. In 1948 McClintock made her most startling discovery of all. Segments of chromosomes could be transposed — switch places on the genome — a phenomenon popularly known as ‘jumping genes’. In the maize plants this produced a mosaic coloured pattern.”

 

“Today, genomic transpositions are recognized as widespread in evolution. It has been estimated that up to half the human genome has undergone such genetic gymnastics.” 

 

“On the occasion of her Nobel Prize, awarded for ‘the discovery of mobile genetic elements’, she had this to say:

 

“The conclusion seems inescapable that cells are able to sense the presence in their nuclei of ruptured ends of chromosomes and then to activate a mechanism that will bring together and then unite these ends, one with another ... The ability of a cell to sense these broken ends, to direct them toward each other, and then to unite them so that the union of the two DNA strands is correctly oriented, is a particularly revealing example of the sensitivity of cells to all that is going on within them... A goal for the future would be to determine the extent of knowledge the cell has of itself, and how it utilizes this knowledge in a ‘thoughtful’ manner when challenged... monitoring genomic activities and correcting common errors, sensing the unusual and unexpected events, and responding to them, often by restructuring the genome. We know about the components of genomes that could be made available for such restructuring. We know nothing, however, about how the cell senses danger and instigates responses to it that often are truly remarkable.”

.

But the data is too extensive at this point – cells have the ability to adjust themselves, and the ability to sense – and time –when/what is needed.

 

“Recent progress in microbiology has shown that an overwhelming majority of DNA changes in the genome are the product of internal regulatory and control networks, not random mutations and incremental “additive” selection. There is also much evidence of various biases in mutational processes (---). Indeed, rapid genome alteration and restructuring can be achieved by a variety of mobile DNA “modules”—transposons (---), integrons, CRISPRs, retroposons, variable antigen determinants, and more (---). It is now also apparent that individual cells have a variety of internal regulatory and control capabilities that can significantly influence cell development and the phenotype. More significant, they may even provide feedback that modifies the genome and affects subsequent generations (---). Particularly significant are the discoveries related to the influence of exosomes, which resemble Darwin’s speculative ideas of pangenesis and internal migratory “gemmules” (Darwin’s term) in reproduction, as Noble (2019) has pointed out. Exosomes also clearly violate the so-called Weismann barrier (the assumption that genetic change is only a one-way process). ..  As Shapiro (2011, 2) emphasizes, “The capacity of living organisms to alter their own heredity is undeniable. Our current ideas about evolution have to incorporate this basic fact of life.”

[Purpose, p. 14]

 

And some of our bio-engineering tools were ‘appropriated’ from processes observed in ‘primitive’ cells (e.g. CRISPR):

 

“Conventional evolutionary theory teaches that targeting genome change is unnatural, a recent human invention. Nonetheless, vertebrates have been doing just exactly that for about 500 million years as they evolved the intricate adaptive immune system that protects us from infections and cancer [--]. Furthermore, last year’s Nobel Prize in chemistry went to two women who pioneered RNA-targeted genetic engineering methods based on sophisticated systems from supposedly primitive prokaryotic cells without nuclei [--]. Bacteria and archaea have probably been using the now famous CRISPRs to defend themselves longer than nucleated eukaryotic cells have existed on Earth” [Shapiro, p.38].

 

And the ability to re-engineer and shift DNA shows up in so many cellular-level interactions. Consider the responses of the ‘simpliest’ of prokaryotes to our immune responses to their invasion:

 

“Although the mammalian adaptive immune system is exceptional in the complexity and specificity of its multiple actions on the antibody-coding loci in our genomes, it is far from unique in using DNA manipulations to modify cell-cell interactions. Even the simplest of prokaryotic cells… rearrange the DNA encoding their surface proteins to alter them so they can escape antibody-guided destruction [--]. The general name for such genome manipulations is antigenic variation. In other words, our immune system is in a constant NGE (natural genetic engineering) arms race with the microbes that try to take over our bodies for their own ends.”  [Shapiro, p.39].

 

His conclusion—having incorporated overwhelming numbers of cases of self-modification—is this:

 

“As I see it, virtually all the major progress in using the most modern tools of genome analysis these last 10 years favors the idea of evolution as an active process of self-modification by organisms endowed with a toolbox of change processes totally inconceivable at the time DNA was identified as the molecular carrier of genetic information in 1953.” [Shapiro, p.41].

 

 

______________________________________________________________________  _________

 

TWO: When all other assemblies of chemical structures DO NOT (!)…

 

As can be seen in many of the quotes above, the ‘something different’ about life is that it  ‘pursues’ something … it pursues food, internal health, resiliency against the outside world, and even expansion of itself further into that external world through reproduction.

 

Life is always hungry…always seeking energy to persist…

 

“In all known cases of self-ordering, dissipative systems that display emergent properties, autocatalysis continues until the conditions for the system’s continuation cease. The major difference between such nonbiological systems and biological systems is not the ability to replicate – given inputs of matter and energy, autocatalytic sets will replicate if split into physically separated spaces. Rather, the major difference is the ability of a biological system to “reach out and manipulate the world on its own behalf” (Kauffinan 2000, 49). A candle flame gutters and dies when the wax is exhausted; it doesn’t search for more. The same is true for a Renard cell, a laser, a hurricane or a Belousov-Zhabotinsky reaction when the conditions for their existence cease.”

[“To Be or Not To Be: Where Is Self-Preservation in Evolutionary Theory?”. Pamela Lyon. In Transitions, p. 109.]

 

 

“By contrast, in conditions of nutrient limitation, a population of Bacillus subtilis will synthesize enzymes to scavenge alternative sources of nutrients (Msadek 1999). If that fails, a portion of the bacterial population suicides through autolysis, which means individual cells break open their membrane and literally spill their guts, providing a temporary source of food for the remaining members of the population in the event conditions are about to change (--). If conditions remain dire, the population commits to sporulation, an irreversible, do-or-die process in which cells transform, over eight hours, into spores capable of resisting injury by heat, chemicals and ultraviolet radiation and remaining dormant (sometimes for years) until life-sustaining conditions return.”

[“To Be or Not To Be: Where Is Self-Preservation in Evolutionary Theory?”. Pamela Lyon. In Transitions, p. 109.]

 

 

“Kauffman is correct. Many complex structures – including networks – can and do arise spontaneously. Indeed, we can find examples of order-for-free all around us. The problem is that such structures do not yet have function, agency, or purpose. They are not yet alive. Self-organization, as mathematicians and physicists use the term, may indeed be necessary for the emergence of biological forms of organization, but as I have argued on a number of occasions, and as Stuart Kauffman now acknowledges, for understanding living processes it is not enough. Despite all our efforts, the critical properties of function, agency, and purpose continue to mark organisms (even if not machines) apart from thunderstorms – indeed, apart from all the emergent phenomena of nonlinear dynamical systems, remaining conspicuously absent from the kinds of systems with which physics deals. An account of how properties of this sort might emerge from the dynamics of effectively homogeneous systems of simple elements, however complex the dynamics of their interaction might be, continues to elude us. Such properties seem clearly to require an order of complexity that goes beyond that which spontaneously emerges from complex interactions among simple elements – a form of complexity that control engineers have been struggling to characterize ever since the 1940s, and that Warren Weaver, Herbert Simon, and now John Mattick and John Doyle, have dubbed organized complexity.”

[“To Be or Not To Be: Where Is Self-Preservation in Evolutionary Theory?”. Pamela Lyon. In Transitions, p. 109.]

 

 

Life is always seeking something, always has a purpose

 

Modern biologists have long recognized that the core difference between life and non-life was purpose (or ‘teleology’):

 

“Purposefulness, or teleology, does not exist in nonliving nature. It is universal in the living world. It would make no sense to talk of the purposiveness or adaptation of stars, mountains, or the laws of physics. Adaptedness of living beings is too obvious to be overlooked.… Living beings have an internal, or natural, teleology. Organisms, from the smallest bacterium to man, arise from similar organisms by ordered growth and development. Their internal teleology has accumulated in the history of their lineage. On the assumption that all existing life is derived from one primordial ancestor, the internal teleology of an organism is the outcome of approximately three and a half billion years of organic evolution.… Internal teleology is not a static property of life. Its advances and recessions can be observed, sometimes induced experimentally, and analyzed scientifically like other biological phenomena (Dobzhansky et al., 1977, 95–96).

 

“Many other theorists over the years have expressed similar views, as Samir Okasha has documented in his book-length study, Agents and Goals in Evolution (2018; see also Walsh, 2015). For instance, the Nobel biologist Jacques Monod (1971, 9) concluded that “one of the most fundamental characteristics common to all living things [is] that of being endowed with a project, or a purpose.” Likewise, the biologist Ernst Mayr, one of the founding fathers of the so-called modern synthesis in evolutionary biology, wrote “goal directed behavior … is extremely widespread in the natural world; most activity connected with migration, food-getting, courtship, ontogeny, and all phases of reproduction is characterized by such goal orientation” (Mayr, 1988, 45).

[Purpose, p. 12]

 

 

“The huge gulf that separates physics and biology – the realm of atoms and molecules from that of living organisms – is unbridgeable without fundamentally new concepts. Living organisms have goals and purposes – the product of billions of years of evolution – whereas atoms and molecules just blindly follow physical laws. Yet somehow the one has to come out of the other.” [Davies, Demon, pp. 1-2]

 

 

 

And that has even become the ‘ground-zero premise of evolutionary biology”:

 

“The ground-zero premise of evolutionary biology is that life is, in essence, a “survival enterprise.” Living organisms are inherently contingent, dynamic phenomena that must actively seek to survive and reproduce. This existential problem requires that they must be goal-directed in an immediate, proximate sense.”

[Purpose, p. 15]

 

“All models of life-origin, whether Protometabolism-First or pre-RNA /  RNA World early informational self-replicative models, encounter the same dead-end: no naturalistic mechanism exists to steer objects and events toward eventual functionality. No insight, motive, foresight or impetus exists to integrate physicochemical reactions into a cooperative, organized, pragmatic effort. Inanimate nature cannot pursue the goal of homeostasis; it cannot scheme to locally and temporarily circumvent the 2^nd Law. This deadlock affects all naturalistic models involving hypercycles, composomes and chemotons. It precludes all spontaneous geochemical, hydrothermal, eutectic, and photochemical scenarios. It affects the Lipid, Peptide and Zinc World models. It pertains to Co-evolution and all other code-origin models. No plausible hypothetical scenario exists that can convert chance and/or necessity into an organized protometabolic scheme. “

[The First Gene, David L. Abel, Editor 2011, pp 231-286]

 

 

 

 

Life is working, never getting a ‘day off’ – ceaseless activity until its “time in the sun is up”…and then it releases its resources to the next generation of life.

 

1.      Within the cell, when components are damaged beyond repair, the process of autophagy identifies those components and ’de-commissions’ them (stopping them from damaging others), and either recycles/reuses their internal materials (.e.g the salvage pathways) or disposes of them to the outside world.

2.      When enough internal processes of the cell become ineffective to maintain cell health (e.g. homeostasis) and repair mechanisms cannot remediate them, then the cell will schedule it own shutdown/death (apoptosis)—and it becomes then ‘just another group of chemicals’ that degrades and dissipates according to the natural processes of chemistry and physics.

3.      When cells in a cooperative arrangement detect that the food supply is not enough to support the groups, some volunteers sacrifice themselves to become food for the others [example given above of Bacillus subtilis.]

 

All of these processes require the complex signaling and metabolic ‘interventions’ described above.

 

No collection of non-living molecules does this…all the examples of auto-catalytic systems and crystalline structures and emergent vortices do not come close. The two are not the same….

 

 

__________________________________________________________ __________

 

THREE: And when we have no real explanation of how they got here (?!) …

 

We have no plausible idea how it GOT HERE (not that any understanding of that would make it less ODD / UNEXPECTED in its existence).

 

By all admission, ‘origin of life’ theories seem less plausible with each new, brilliant experiment and with each further discovery of cellular processes. The optimism of the past—at being able to synthesize life in the lab—has given way to a rather bleak pessimism (even given the almost hubric optimism of good scientists-lol) of the main researchers in the field.

 

We do not need to get into the ‘origin of life’ debate here—all we need to note (for my purposes here) is that all the brilliant science research that has been done in this area has only served to support the position that life (and most of the components inside the cell) are “of inexplicable origin”… Consider just a few summary statements by those working inside the field and  in adjacent fields.

 

Koonin makes a strong statement about how difficult this issue is:

 

“In the preceding chapter, we discussed possible scenarios for the origin of cells and (hopefully) reached some degree of plausibility with the primordial Virus World scenario of cellular evolution. However, this was all about relatively late stages of evolution, at which replication of the genetic material and translation yielding diverse proteins were already well established. All these models seem to be of dubious value unless we develop some kind of explanation for the origin of the fundamental processes of information transmission.

 

“The origin of life is the most difficult problem that faces evolutionary biology and, arguably, biology in general. Indeed, the problem is so hard and the current state of the art seems so frustrating that some researchers prefer to dismiss the entire issue as being outside the scientific domain altogether, on the grounds that unique events are not conducive to scientific study. However, this position appears deeply unsatisfactory, especially because, although life certainly evolved only once on this planet (---), we have no idea just how unique (or otherwise) it is in our universe as a whole. If one does accept the origin of life as a scientific issue, then there seems to be no denying that it is a problem of overwhelming importance before which all other questions in biology are relatively mundane.” [p 351]

 

This is a fairly strong statement, but the data seems to support it…

 

Results not encouraging so far…

 

“Francis Crick once described the origin of life as ‘almost a miracle, so many are the conditions which would have had to have been satisfied to get it going’. And it’s true that the more ‘miraculous’ life appears to be, the harder it is to figure out how it can have started. In 1859 Charles Darwin’s magnum opus On the Origin of Species first appeared. In it he presented a marvellous account of how life has evolved over billions of years from simple microbes to the richness and complexity of Earth’s biosphere today. But he pointedly left out of his account the question of how life got started in the first place. ‘One might as well speculate about the origin of matter,’ he quipped in a letter to a friend. Today, we are not much further forward.”  [Davies, Demon, p. 167]

 

“Armed with a basic notion of the chemical setting (no oxygen!), scientists have spent decades trying to re-create conditions in the laboratory that might illuminate the first chemical steps on the long pathway to life, following Miller’s pioneering efforts in 1953. Many subsequent pre-biotic synthesis experiments have been done but, to be honest, they don’t get very far, in spite of the dedication and ingenuity of the scientists. By the standards of biological molecular complexity, these attempts barely make it to first base.”

 [Davies, Demon, p 172]

 

“Focusing on chemical correlates has yielded limited progress in solving the origin of life, even after many decades of effort.” [Walker, p. 50]

 

“RNA World hypothesis. This model proposes that life started with RNA, as opposed to DNA (deoxyribonucleic acid), as the genetic material. During the last few decades, the RNA World has been considered the leading hypothesis for the origin of life on Earth. Gerry studies the in vitro evolution of RNA molecules to understand potential mechanisms of chemical evolution in the putative RNA World. He and his colleagues have demonstrated amazing capabilities in RNA, such as the ability for self-replication and evolution under controlled conditions. Because RNA chemistry isolated and evolved in a test tube can fulfill so many functions of living biochemistry, it is understandable one might arrive at a definition of life as a self-sustaining chemical system capable of Darwinian evolution. A lot of people use this definition and like it. But at the same time, like all definitions for life, it fails to deliver on solving the hardest problems. It has not allowed us to prove a mechanism for the origin of life nor design new instruments to search for and measure the presence of alien life on another world. … Let’s first focus on the notion of “self-sustaining.” In vitro evolution proceeds by taking a sample from one test tube and transferring it to another, and then another, to simulate successive rounds of evolutionary selection. Because evolution occurs only by intervention of the experimenter, it requires continual human input to sustain an evolving population of RNA. Most people do not feel comfortable referring to these systems as “life” because they are not self-sustaining and they require human intervention. Most people thus take the stance, like the NASA working group did, that such systems should be excluded.” [Walker, pp. 10-11]

 

“So, according to this view, it is easy to define life: life is information that replicates itself. … If life is information, where did this information come from initially? We asked this question in chapter 7, and while it may appear at first that replacing the question “What is the origin of life?” with “What is the origin of information?” trivializes the search for our origins, it turns out that the question is still hard. According to what we know today, the amount of information  necessary (and sufficient) to encode that information’s own replication cannot simply emerge by chance. And assuming that the first form of life arrived  on Earth from somewhere else in the solar system or galaxy does not solve the problem, because the mathematics of the chance emergence of information does not change if we move from one planet to another. This does not mean that the emergence of life from nonlife is impossible, it just means that  we have yet to discover the pathway that allows information growth in a system  where Darwinian evolution has yet to take hold. …“ [Adami, p. 507]

 

“Selfishness cannot simply be assumed, however. That a chemical system developed the impetus not merely to replicate, like a crystal, but to replicate specific sequences of complex molecules and persist against existential threat, are phenomena that demand explanation. None of the inorganic self-ordering, autocatalytic, dissipative structures known to contemporary science does this (--). A crystal, a candle flame, a hurricane, or a Benard cell does not seek resources when the material conditions for continued catalysis runs out; they cease. Living things do so until all options are exhausted. Some of the simplest organisms engage in surprisingly elaborate behaviors to forestall cessation.” [“To Be or Not To Be: Where Is Self-Preservation in Evolutionary Theory?”. Pamela Lyon. In Transitions, p. 105.]

 

“The uncritical assumption of selfishness creates a fundamental instability in much current work on the evolutionary transitions and origins of life. Some of the leading transitions narratives assume selfishness explicitly (Michod and Roze 1997) or implicitly (Maynard Smith and Szathmary 1995) at their foundation. All current origin-of-life scenarios of which I am aware also appear to presume the emergence of selfishness, or the kind of self-organized organized complexity that supports the attribution of similar concepts, at a very early stage, well before cells appear. Since this assumption is unsupported, origins narratives remain incomplete until the emergence of self-preserving behavior is explained.”

[“To Be or Not To Be: Where Is Self-Preservation in Evolutionary Theory?”. Pamela Lyon. In Transitions, p. 106.]

 

“The degree of empirical support for the RNA World hypothesis is not central to my argument. However, Orgel’s pessimistic estimation of the evidence supporting his hypothesis places in useful perspective unarticulated assumptions about system-preserving behavior in the development of life, so I will briefly outline it here. In his last review of progress on the RNA World hypothesis before his death in 2007, Orgel reports that “there is at present no convincing, prebiotic total synthesis of any of the nucleotides” necessary to support RNA synthesis (Orgel 2004, 108; my italics). Further, no evidence has yet emerged linking ribozymes, “the smoking gun that ... led to the more general acceptance of the RNA World hypothesis,” to genetic transcription or RNA replication (Orgel 2004, 113). “[A]biotic synthesis of RNA is so difficult,” Orgel concludes, “that it is unclear that the RNA World could have evolved de novo on the primitive Earth” at all (100), a conclusion first advanced by Cairns-Smith 30 years ago.

… Thus, in the opinion of one of its leading advocates, scientific investigation of the RNA World hypothesis has yielded much interesting chemistry in the past 40 years but little progress toward an adequate explanation for the origins of informational molecules, much less life. The language Orgel uses to sketch “some consequences of the RNA World hypothesis” is all the more notable, therefore, because an informational molecule is still only a hope, not a reality. It is the sort of language used commonly in origins and transitions narratives….”

[“To Be or Not To Be: Where Is Self-Preservation in Evolutionary Theory?”. Pamela Lyon. In Transitions, Page 110.]

 

“For all Darwin’s indisputable achievements, he left a sizable problem for future generations to solve: namely, the question of how the first “primordial form, into which life was first breathed,” from which “all the organic beings which have ever lived on this earth have descended” – that “simple beginning” from which “endless forms most beautiful and most wonderful have been, and are being, evolved” – first came into existence.” 

[“Self-Organization, Self-Assembly, and the Inherent Activity of Matter” in Transformations, 1^st paragraph of the chapter.]

 

“However, this is about all the good news; the rest is more like a sobering cold shower. For all the advances of “ribozymology,” no ribozyme polymerase comes close to what is required if we are to accept an RNA-only replicator system as a key intermediate stage in the evolution of life. Nor are any ribozymes capable of catalyzing the synthesis of nucleotides or even their sugar moieties. Even sweeping all these problems under the proverbial rug, the path from a putative RNA World to the translation system is incredibly steep. The general idea of a function(s) for abiogenic amino acids and possibly peptides in the RNA World, such as the role of ribozyme cofactors, appears fruitful and is compatible with experimental data. Nevertheless, breaking the evolution of the translation system into incremental steps, each associated with a biologically plausible selective advantage, is extremely difficult even within a speculative scheme let alone experimentally. The triplicase / protoribosome hypothesis is attractive as an attempt to explain the origin of translation and replication in one sweep, but is this scenario realistic? The triplicase itself would have to be an extremely complex, elaborate molecular machine, leaving one with the suspicion that, all its attraction notwithstanding, the triplicase might not be the most likely solution to the origin of translation problem. …  All things considered, my assessment of the current state of the art in the study of the origins of replication and translation is rather somber. Notwithstanding relevant theoretical models and suggestive experimental results, we currently do not have a credible solution to these problems and do not even see with any clarity a path to such a solution.”  [Koonin, pp. 376-377].

 

 

“As pointed out earlier, the overall situation in the origin of life field appears rather grim. Even under the (highly nontrivial) assumption that monomers such as NTP are readily available, the problem of the synthesis of sufficiently stable, structurally regular polymers (RNA) is formidable, and the origin of replication and translation from such primordial RNA molecules could be an even harder problem. …  The emergence of the first replicator system, which represented the “Darwinian breakthrough,” was inevitably preceded by a succession of complex, difficult steps for which biological evolutionary mechanisms were not accessible. Even considering environments that could facilitate these processes, such as networks of inorganic compartments at hydrothermal vents, multiplication of the probabilities for these steps could make the emergence of the first replicators staggeringly improbable.” [Koonin, p. 382]

 

”However, the origin of life—or, to be more precise, the origin of the first replicator systems and the origin of translation—remains a huge enigma, and progress in solving these problems has been very modest—in the case of translation, nearly negligible. Some potentially fruitful observations and ideas exist, such as the discovery of plausible hatcheries for life, the networks of inorganic compartments at hydrothermal vents, and the chemical versatility of ribozymes that fuels the RNA World hypothesis. However, these advances remain only preliminaries, even if important ones, because they do not even come close to a coherent scenario for pre-biological evolution, from the first organic molecules to the first replicator systems, and from these to bona fide biological entities in which information storage and function are partitioned between distinct classes of molecules (nucleic acids and proteins, respectively). In my view, all advances notwithstanding, evolutionary biology is and will remain woefully incomplete until there is at least a plausible, even if not compelling, origin of life scenario.” [Koonin, p. 417]

 

“This information hierarchy—DNA to RNA to proteins—was worked out in the 1950s-60s and allowed scientists to comprehend the general mechanism by which the self-maintenance of organisms occurs. Nevertheless, this understanding does not explain the origin of such a mechanism or how such a system could evolve in the first place. By understanding the central dogma, we may begin to imagine and test experimentally the potential prebiotic chemistry that could have provided the foundation for the eventual emergence of something so sophisticated. [Prebiotic, p. 41]

 

“mRNA molecules are produced using DNA templates via transcription. mRNA is read out using ribosomes to make proteins via translation. It remains unknown how these processes originated.” [Prebiotic, p. 46]

 

 

Lab versus “messy earth”

 

“For the majority of the history of prebiotic chemistry research (and organic synthesis as a whole), most reactions have been carried out using stepwise protocols starting with pure reagents, commensurate with the teachings and techniques for what might be termed traditional organic chemistry. There is a growing recognition by the prebiotic chemistry research community that geochemical environments would have been ‘messy; leading to complex mixtures, and that this complex chemistry, which may be crucial for the emergence of life-like behaviours needs to be investigated experimentally.” [Prebiotic, p. 6]

 

 

“The fundamental problem is not the simplicity of the components in these experiments. It is something far deeper. To attain even the modest successes announced so far requires special equipment and technicians, purified and refined substances, high-fidelity control over physical conditions — and a big budget. But above all, it needs an intelligent designer (aka a clever scientist). The organic chemist must have a preconceived notion of the entity to be manufactured. I’m not denigrating the scientists involved or the glittering promise of the field of synthetic biology, only its relevance to the natural origin of life. Astrobiologists want to know how life began without fancy equipment, purification procedures, environment-stabilizing systems and — most of all — without an intelligent designer. It may turn out that life is indeed easy to make in the lab but would still be exceedingly unlikely to happen spontaneously in the grubby and uncertain conditions available to Mother Nature. After all, organic chemists can readily make plastics, but we don’t find them occurring naturally. Even something as simple as a bow and arrow is straightforward for a child to make, but would never be created by an inanimate process. So just because we might (one day) find life easy to create does not of itself demonstrate a cosmic imperative.” [Davies, Demon, pp. 178-179]

 

“There is a long history of what might be called ‘molecular Darwinism’ in which ‘naked’ molecules are able to replicate with varying efficiency and natural selection filters out the best. The so-called RNA world theory falls into this category. Though these studies are instructive, they are very contrived and require carefully managed human intervention (e.g. to prepare materials, to do the selecting) to accomplish anything. Relevance to the natural world is far from obvious.” [Davies, Demon, p. 183, note 2]

 

“Ribonucleic acid (RNA) holds a special place in origins-of-life research, because its sequence provides both a potential mechanism for storing information as well as carrying out catalysis and other functions. In extant biology, however, the synthesis of these biopolymers including RNA requires a suite of sophisticated (highly evolved) proteins as well as the ribosome, which a priori would not have existed during the early stages of prebiotic chemistry” [Prebiotic, p. 117]

 

 

The Ratchet problem:

 

“As I have mentioned, a basic unknown about the pathway from non-life to life is whether it was a long, steady slog up a pre-biotic version of Mount Improbable, or whether it took place in fits and starts, with long periods of stasis interrupted by great leaps forward (or upward, in this metaphor). Given that Mount Improbable is so incredibly high, it won’t do for a chemical mixture to attain a toehold in the foothills only to slide back down again. There has to be some sort of ratcheting effect to lock in the gains and limit the losses while the system hangs out for the next step. But ideas like this, which seem sensible enough, run into the problem of teleology. A chemical soup doesn’t know it’s trying to make life – a chemical soup doesn’t know anything at all – so it won’t act to protect its hard-won complexity from the ravages of the second law of thermodynamics. Scenarios in which chemistry ‘strives’ towards life are patently absurd. The same problem doesn’t occur once life gets going, because natural selection can ratchet up the gains and DNA storage can lock them in. But chemistry without natural selection has no recourse to such mechanisms…” [Davies, Demon, pp. 172-175]

 

 

“The backsliding problem afflicts almost all studies of the complexification pathway to life. There are many clever experiments and theoretical analyses demonstrating the spontaneous formation of complexity in a chemical mixture, but they all hit the same issue: what happens next? How does a chemical broth build on some spontaneously emerging complexity to then ramp up to something even more complex? And on and on, until the summit of the pre-biotic Mount Improbable is reached? The most promising break-out from this straitjacket comes from work on ‘autocatalytic’ chemical cycles. The idea here is that certain molecules, say A and B, react to make other molecules, C, that happen to serve as catalysts to accelerate the production of A and B. There is thus a feedback loop: groups of molecules catalyse their own production. Scaling this up, there could be a vast network of organic molecules forming a quasi-stable system of autocatalysis, with many interlocking feedback loops, combining in a tangled web of reactions that is self-sustaining and robust. All this is easy to state in words, but are there such chemical systems out there? Yes, there are. They are called living organisms and they deploy all the aforementioned features. But now we are going round in circles, because we want to ascertain how all this marvellous chemistry can take place before life. We can’t put the solution by hand into the problem we are trying to solve and then claim to have solved it.” [Davies, Demon, pp. 172-175]

 

“Multiple rounds of prebiotic RNA template-directed synthesis still remain a challenge but are necessary in order to have a system capable of sustained replication and hence Darwinian evolution. The biggest obstacle to achieving this is the fact that a successful round of template copying is prone to result in a stable double-stranded structure. In order for another round of template-directed synthesis to begin, the two strands must be separated and remain separated long enough for on-template  polymerization/ligation to take place. The fact that the resulting duplex impedes further rounds of copying is known as the strand inhibition problem. Two hybridized strands can potentially be separated simply by raising the temperature past the melting points; however, high temperatures also prevent Watson-Crick pairing of the activated mono- and oligonucleotides.” [Prebiotic, p. 132]

 

“Another rather ingenious strategy for achieving multiple rounds of RNA synthesis takes advantage of chimeric templates… however, the resulting RNA-chimeric duplex is not as stable as the corresponding pure RNA duplex. This weaker duplex means the chimeric strand can be readily displaced by two, smaller complementary RNA oligonucleotides…. Achieving multiple rounds of RNA copying still has challenges to be overcome but is currently an active area of research. Success would open the door to producing chemical systems which can begin to undergo Darwinian evolution in the laboratory in a potentially prebiotic manner.” [Prebiotic, p. 132]

 

 

“The Fitness Landscape before Evolution  The central problem that we have to surmount when it comes to understanding the origin of life is that there appears to be an insurmountable gap between  the minimum amount of information it takes to self-replicate, and the amount  of information that can appear by chance, even if we account for a biased  monomer distribution that can deliver a significant amount of information  “for free,” as it were, via the enhancement factor the bias provides. In order to bridge this gap, we need to uncover a dynamical process that will drive  information to higher levels in a non-equilibrium fashion, perhaps in a ratchet manner (---). To this day, no one has identified such a process. But even if we could identify it, can such a process reach the flanks of  the fitness peaks of the primordial fitness landscape: the landscape of the simplest self-replicators?” [Adami, p. 403]

 

 

Chicken or Egg problem

 

“Obviously, when considering the origin of the first life forms, one faces the proverbial chicken-and-egg problem: What came first, DNA or protein, the gene or the product? In that form, the problem might be outright unsolvable due to the Darwin-Eigen paradox: To replicate and transcribe DNA, functionally active proteins are required, but production of these proteins requires accurate replication, transcription, and translation of nucleic acids. If one sticks to the triad of the Central Dogma, it is impossible to envisage what could be the starting material for the Darwin-Eigen cycle. Even removing DNA from the triad and postulating that the original genetic material consisted of RNA (thus reducing the triad to a dyad), although an important idea (---), does not help much because the paradox remains. For the evolution toward greater complexity to take off, the system needs to somehow get started on the Darwin-Eigen cycle before establishing the feedback between the (RNA) templates (the information component of the replicator system) and proteins (the executive component).

[Koonin, p. 360]

 

“The crucial question in the study of the origin of life is how the Darwin-Eigen cycle started—how was the minimum complexity that is required to achieve the minimally acceptable replication fidelity attained? In even the simplest modern systems, such as RNA viruses with the replication fidelity of only about 10^(-3) and viroids that replicate with the lowest fidelity among the known replicons (about 10^(-2) ---), replication is catalyzed by complex protein polymerases. The replicase itself is produced by translation of the respective mRNA(s), which is mediated by the immensely complex ribosomal apparatus. Hence, the dramatic paradox of the origin of life is that, to attain the minimum complexity required for a biological system to start on the Darwin-Eigen spiral, a system of a far greater complexity appears to be required. How such a system could evolve is a puzzle that defeats conventional evolutionary thinking, all of which is about biological systems moving along the spiral; the solution is bound to be unusual.” [Koonin, p. 353]

 

“In living things, most chemical activity is handled by proteins. Metabolism — the flow of energy and material through organisms — is necessary for life to achieve anything, and proteins do the lion’s share of metabolic work. If life got started (as Prigogine believed) via elaborate energy-driven chemical cycles, then proteins must have been early actors in the great drama of life. But on their own, proteins are largely useless. The all-important organization of life requires a great deal of choreography, that is, some form of command-and-control arrangement. That job is done by nucleic acids (DNA and RNA). Life as we know it involves a deal struck between these two very different classes of molecules: nucleic acids and proteins. The conundrum as most scientists see it is the chicken-and-egg nature of life: you can’t have one without the other. Without a legion of proteins to fuss around it, a molecule of DNA is stranded. In simplistic terms, the job descriptions are: nucleic acids store the details about the ‘life plan’; proteins do the grunt work to run the organism. Both are needed.” [Davies, Demon, p. 22]

 

”The “chicken—egg relationship” between genes and proteins: The so-called “chicken—egg relationship” has made it difficult to solve the mystery of the origin of life for many years. In such a situation, the RNA world hypothesis, which assumes that first life arose from the RNA world, which was formed by the self-replication of RNA, was proposed by Gilbert in 1986 [---]. However, it would be principally impossible to solve the from the standpoint of this hypothesis because any gene encoding a mature protein could never be formed in the absence of a target protein or in the absence of protein, even if RNA could be produced on primitive Earth.” [Ikehara, K. “How Did Life Emerge in Chemically Complex Messy Environments?” Life 2022, 12, 1319]

 

“So an inevitable (even if perhaps counterintuitive) conclusion from the comparative analysis of ancient paralogous relationship between protein components of the translation system is that, with the interesting exception of the core ribosomal proteins, all proteins that play essential roles in modern translation are products of a long and complex evolution of diverse protein domains. Here comes the Catch-22: For all this protein evolution to occur, an accurate and efficient translation system is required. This primordial translation system might not need to be quite as good as the modern version, but it seems a safe bet that it must have been within an order of magnitude from the modern one in terms of fidelity and translation rates to make protein evolution possible. However, from all we know about the modern translation system, this level of precision is unimaginable without a complex, dedicated protein apparatus…. Thus, the translation system presents us with the “Darwin-Eigen paradox” that is inherent to all thinking on the emergence of complex biological entities: For a modern-type, efficient, and accurate translation system to function, many diverse proteins are required, but for those proteins to evolve, a translation system almost as good as the modern one would be necessary. There seems to be only one conceivable solution to this paradox—namely, a (partial) refutation of the first part of the opposition: We are forced to conclude that a translation system comparable to the modern one in terms of accuracy and speed functioned without many proteins, possibly without any proteins at all. Hence, the existence of a complex, elaborate RNA World, in which a primitive version of the Darwin-Eigen cycle was already operating, can be conjectured from the comparative analysis of the translation system components.” [Koonin, p. 359]

 

(A special version of the chicken-and-egg problem occurs with eukaryotes. Certain error-control systems had to be in place when euk’s appeared (“co-evolved”), but do not show up in other life forms:

 

“As we discussed in great detail in Chapter 7, eukaryotes possess an important information-processing step that effectively has no counterpart in prokaryotes: splicing of primary transcripts. The accompanying quality control system apparently has evolved concomitantly with eukaryogenesis: the nonsense-mediated decay (NMD) machinery which recognizes and destroys aberrant mRNAs that contain in-frame stop codons in exons other than the last, 3’-terminal exon of the coding sequence (---).” [Koonin, pp. 279f]

 

 

And there were ‘hostile’ elements working AGAINST even getting started…

 

Even the elements important to life’s existence noted in the earlier installment, can WORK AGAINST any putative pre-biotic processes thought to be involved in life’s emergence.

 

For example, oxygen – critical to much of life’s metabolism on earth today – destroys most things. And a ‘reducing’ atmosphere – believed by many OOL (Origin Of Life) researchers to be a requirement for the origination of primitive life– would kill most air-breathers today. So, Davies [Demon, pp. 170-171]:

 

“Shifting the cradle of life from Earth to somewhere else doesn’t much advance the more important question of what geological setting would be conducive to producing life. Many scenarios have been touted: deep ocean volcanic vents, drying lagoons, pores in sub-ocean rocks ... the list is long. About the only thing everyone agrees on is that oxygen gas would have been a frustrating factor. Today, complex organisms require oxygen for their metabolism, but this was a late development. On Earth, there was very little free oxygen in the atmosphere before about 2 billion years ago, and present levels were not attained until within the last billion years. Oxygen may feel good to breathe, but it is a highly reactive substance that attacks and breaks down organic molecules. Aerobic life has evolved all sorts of mechanisms to cope with it (such as anti- oxidants). Even so, reactive oxygenic molecules regularly damage DNA and cause cancer. When it comes to the origin of life, free oxygen is a menace. “

 

 

And water – so essential to life as we know it – would have been a major ‘frustrating factor’ in pre-biotic processes, since it tends to ‘dissolve stuff.

 

“Life as we know it would not exist without water. However, water molecules not only serve as a solvent and reactant but can also promote hydrolysis, which counteracts the formation of essential organic molecules. This conundrum constitutes one of the central issues in origin of life. Hydrolysis is an important part of energy metabolism for all living organisms but only because, inside cells, it is a controlled reaction.” [“The ambivalent role of water at the origins of life”, Vieira, Kleinermanns, Martin, Preiner. FEBS Lett. 2020 Sep]

 

“The “water paradox” is a crucial problem in the research on the prebiotic chemical evolution towards the emergence of life: It states that although aqueous environments are essential for life, they impede key chemical reactions such as nucleotide  polymerization. In aiming to overcome this paradox various hypotheses have been proposed, including scenarios based on alternative solvents like formamide, condensing agents like cyanamide, high temperatures (~160°C) or approaches based on wet/dry cycles. However, when appraising the prebiotic plausibility of such scenarios general weaknesses appear. Besides the fact that all known life manages the water paradox without needing such proposed conditions, evolutionary conservatism – the principle that evolution builds on existing pathways – indicates that the same physicochemical effects were probably involved in the abiotic origin of biopolymers as now being tapped by life via complex enzymes.” [“Natural Nanofluidic Environments as Prebiotic Reaction Vessels: Abiotic RNA formation in temporal nanoconfined water”, Frank Trixler, NORCEL Institute.]

 

But not only does water ‘IMPEDE” formation, but it REVERSES it too:

 

“The fact that water favours the decomposition of RNA and peptides back into their monomer components, as well as other hydrolysis reactions in prebiotic chemistry, is sometimes referred to as the water problem. There is every indication, however, that water is necessary for life, but at the same time, water is constantly working against polymerization.” [Prebiotic, pp. 3-4]

 

 

 

A special case is the ‘space chemistry, where it has been argued that bio-active molecules arrived from space—to jump start life:

 

“Finally, the results obtained from the examination of the space chemistry should be summarized. The most conspicuous negative result is the fact that numerous compounds that play a fundamental role for a successful CE were not found. Here, the following compounds should be mentioned: several prAAs such as Arg, His, and Cys, and oligopeptides; furthermore, the nucleobase cytosine, any kind of nucleosides, nucleotides, and oligonucleotides; last but not least, unsubstituted long alkanols or alkanoic acids which are needed for the formation of lipid membranes are extremely rare compared to the methyl substituted analogs. Even, when traces of some of these compounds will be detected in the future, such findings will not change the conclusion that the space chemistry was and is far from supporting a CE. This conclusion is confirmed by the fact that the space chemistry creates large amounts of chemicals that are unfavorable or even a definite obstacle for a CE. Such compounds are large amounts of non-prAAs and imino acids, large amounts of formic acid, alkanoic acids, hydroxy acids, and even sulfonic acids.”

[Kricheldorf, Hans R.. Life by Chemical Evolution?: A Review and Evaluation of Experiments and Hypotheses (pp. 417-418). Springer Berlin Heidelberg. Kindle Edition.]

 

But these are attacks on ‘life’ before it gets started, and there are many, many more attacks ONCE ITS HERE (e.g. multiple mass extinctions of early life on our planet) to talk about later.

 

 

…………………………………..

 

But even if this trend reversed eventually, and they could do it in a seriously constrained lab with zero contaminants, and incredibly precise control operations, that would be (1) unrepresentative of earth conditions as far from “lab-like” conditions as possible ; (2) require all these test tubes to be co-located and simultaneously/sequentially run, and (3) STILL not reduce the shock from the ‘how is it STILL HERE’ (given all the assaults on it throughout early earth history) question.

 

The most recent (and brutally honest) assessment/review of all the chemical experiments and hypotheses that I have found is Life by Chemical Evolution?: A Review and Evaluation of Experiments and Hypotheses, Springer:2025. By Hans R. Kricheldorf. (of the Institute for Technical and Macromolecular Chemistry, Hamburg Germany).

 

 

After giving the history of the demise of the ‘prebiotic soup’ hypothesis, he makes this observation about its ‘resistance to decay’, in his summary chapter:

 

“Nonetheless, it is amazing that even after the year 2000, the prebiotic soup hypothesis still plays a role as standard scenario for a CE, which yielded a living cell starting out from a mixture of simple molecules such as CO₂, N₂, H₂, and H₂0. This view is above all characteristic for biologists as may be demonstrated by a comment of Ribas de Pouplana in his book “The genetic code and the origin of life” (Ribas de Poublana 2004):

 

“The most widely accepted scenario for the transition from abiotic to biotic chemistry is that the simple monomeric compounds present in the prebiotic soup somehow underwent polymerization, perhaps with the assistance of clays and minerals and formed longer and longer chains or polymers, which over time became increasingly more complex with respect to both their structure and their properties.”

 

In this way, the wonder of the primordial soup as the birthplace of life will be preserved for eternity, at least for laymen of chemistry.

 

 

He points out later that there is no reason to believe that CE (Chemical Evolution) happened:

 

“Finally, the fundamental problem should be discussed, namely the question, why a CE on the early Earth has resulted in the formation of a living cell. Even, when the number of model reactions demonstrating how individual steps of the CE might have occurred will further increase, the knowledge of hundreds of individual reactions does not necessarily explain, why a CE followed the road map toward a living cell. Increasing complexity of groups of molecules also means increasing diversity for the entire pool of organic compounds on Earth, but the driving force for an increasing diversity is a gain of entropy. This correlation is best and clearly demonstrated by the “space chemistry.” However, a living cell practices a different strategy, it maintains thermodynamically instable, kinetically controlled processes and compounds against a gain of entropy by permanent consumption of (sun) energy.”

 

 

He makes the point that belief in the confluence of all factors at the same time (against the evidence) is essentially a ‘hypothesis of a fortunate coincidence’—and not a scientific theory—especially when contraindicated by polymer chemistry:

 

“The hypothesis of a fortunate coincidence or contingency is for three reasons not an acceptable hypothesis of CE.

 

“First, scientific research concerns discovery evaluation and application of laws of nature. A law of nature is evident from the reproducibility of (experimental) observations which are reproducible independently of time, location, and researcher. Yet, singular events are per definition not part of a law of nature, and thus outside the reach of scientific methods.

 

“Second, it has not been demonstrated yet that all the components needed for the formation of a living were simultaneously present on the early Earth, regardless whether the primordial soup or a compartment concept is taken into account. The experiments and observation listed in the preceding chapters rather suggest that a more or less simultaneous evolution of homochiral proteins, RNAs, and amphiphilic molecules forming stable vesicles was not possible. When the RNA world hypothesis is taken into account and when an independent evolution of proteins is ignored, one still needs a strong belief in chemical miracles to assume that those RNAs needed for the production of bioactive proteins were formed in significant quantities, came together and recognized that they had to cooperate for the production of useful proteins.

 

“Third, it requires again a strong belief in wonders to expect that the problem of homochirality was solved by a chance event. Even when one concedes that a fortunate event has accumulated homochiral biopolymers, the racemization would have destroyed the homochirality within a short time except at temperature around or below 0 degrees C.”

 

 

When he get gets around to stating his position, he is blunt about what he sees the data pointing to:

 

“The reader would presumably like to know what is final conclusion of the author. In short, the author is not able to reach a final decision. The hypothesis of a CE is a fascinating vision which (as pointed out below) allows for a consistent interpretation of the structure of the universe, but there are so many open questions and unsolved fundamental problems that the author is not convinced yet that a CE beginning with simple gases and ending up with a living cell has really taken place.”

 

He points out that researcher optimism about CE is more ‘religious’ or ‘ideological’ than scientific:

 

“A researcher, who is a priori convinced that the hypothesis of CE is true, he takes an ideological stance and not a scientific one. Undirected evolution in combination with chance events is not a scientific approach to the explanation of a CE (because reproducibility is fundamentally impossible) and requires so much belief in miracles as any religion. The hypothesis of a directed evolution is confronted with the question who was the “director,”, or which property of the universe has taught the molecules to follow the pathway to a living cell. This problem is acerbated by the finding that the reductionistic-deterministic concept is not correct as evidenced by the failure of numerous model experiments and by the course of the “space chemistry.”

 

And he states that any non-religious approach has to accept (and explain?) the occurrence of TWO “Big Bangs”—

 

“When the existence of a CE is denied, again a religious and a non-religious answer is possible. The religious answer is the creation of the first cell by a God (Allah, Manitou, etc.). The non-religious view is to say that the design of the universe includes two “Big Bangs,” the first one resulting in the appearance of space, time energy and matter, and a second “Big bang” resulting in the appearance of life with the first cell.”

 

 

__________________________________________________________ __________

 

FOUR: … Nor how life is STILL here!

 

Before the modern era, life has been assaulted multiple times, with devastating results.

 

What are called the ‘mass extinctions’ eliminated species and large segments of all life.

 

“Among the most striking features of the fossil record are the periods of accelerated mass extinctions followed by periods of accelerated mass “originations” (appearances of morphologically novel organisms). The most famous of these episodes is the event that led to the disappearance of dinosaurs at the end of the Cretaceous period 65 MYA. … These mass extinctions occurred at the boundaries between one geological age with its characteristic fauna and another with a different fauna. Raup and Sepkowski first documented the “big five” mass extinctions in 1982:

“Since then, mass extinctions have been identified at other major geological boundaries:”

[Shapiro, pp. 407-408]

 

 

The amount of damage estimated from the largest of these is staggering:

One website listed 44 extinction events (of various scales—not all of which are comparable):

 

https://www.nazaudy.com/list-of-extinction-events

 

Extinction 1 – (3.8 Gya) Archean Eon and the Carbon Genesis

Extinction 2 – (2.4 Gya) Huronian Glaciation, Snowball Earth 1 – Great Oxygenation Event (GOE) – First major Ice Age

Extinction 3 – (650 Mya) Stuartian Glaciation, Snowball Earth 2 – Second Ice Age

Extinction 4 – (542 Mya) End-Ediacaran Extinction

Extinction 5 – (513-517 Mya) End-Botomian Extinction

Extinction 6 – (502-497 Mya) Dresbachian Extinction

Extinction 7 – (488 Mya) Cambrian-Ordovician Extinction

Extinction 8 – (450 Mya) 86% of species lost: (1) Ordovician-Silurian Extinction

Extinction 9 – (428 Mya) Ireviken event

Extinction 10 – (424 Mya) Mulde event

Extinction 11 – (420 Mya) Lau event

Extinction 12 – (375 Mya) 86% of species lost: (2) Late Devonian Extinction episode

Extinction 13 – (305 Mya) Carboniferous Rainforest Collapse

Extinction 14 – (299 Mya) The Lignin breakthrough and demise

Extinction 15 – (272 Mya) Olson’s Extinction

Extinction 16 – (260 Mya) End-Capitanian extinction event

Extinction 17 – (250 Mya) 96% of species lost: (3) The Great Permian Extinction

Extinction 18 – (232 Mya) The Carnian Pluvial Episode (CPE)

Extinction 19 – (200 Mya) 80% of species lost: (4) End of Triassic Extinction

Extinction 20 – (183 Mya) Toarcian turnover

Extinction 21 – (145 Mya) End-Jurassic (Tithonian) extinction

Extinction 22 – (117 Mya) Aptian Extinction

Extinction 23 – (94 Mya) Cenomanian-Turonian boundary event

Extinction 24 – (66 Mya) 76% of species lost: (5) End of Cretaceous and the Dinosaurs

Extinction 25 – (56 Mya) Paleocene-Eocene Thermal Maximum (PETM)

Extinction 26 – (33.9 Mya) Eocene–Oligocene Transition event (EOT)

Extinction 27 – (16.9 Mya) Mid Miocene Climate Optimum (MMCO)

Extinction 28 – (14.5 Mya) Middle Miocene disruption

Extinction 29 – (5.96 Mya) Kapitean-Optian Glacial Event

Extinction 30 – (5.3 Mya) The Zanclean flood

Extinction 31 – (3 Mya) The Great American Biotic Interchange

Extinction 32 – (2.6 Mya) Pliocene–Pleistocene boundary extinction

Extinction 33 – (2.1 Mya) Yellowstone eruption number 1

Extinction 34 – (1.3 Mya) Yellowstone eruption number 2

Extinction 35 – (1.09 Mya) The Gakkel Ridge Caldera

Extinction 36 – (790,000) The Bolaven meteor impact

Extinction 37 – (640,000) Yellowstone eruption number 3

Extinction 38 – (400,000) The Homo species extinctions and fire

Extinction 39 – (130,000 years ago) The Eemian interglacial

Extinction 40 – (74,000 years go) The Toba eruption

Extinction 41 – (46,000 years ago) Quaternary extinction, Australian Megafauna disappearance

Extinction 42 – (39,000 years ago) Campanian Ignimbrite eruption

Extinction 43 – (26,500 years ago) Oruanui eruption

Extinction 44 – (24,000 years ago) end of Neanderthals

Extinction 45 – (14,000 years ago) Quaternary extinction, North America Megafauna disappearance

Extinction 46 – (13,000 years ago) Lake Missoula drainage

Extinction 47 – (12,000 years ago) The Younger Dryas

Extinction 48 – (11,500 years ago) The Sundaland Submerge

Extinction 49 – (11,000 years ago) Quaternary extinction, South America Megafauna disappearance

Extinction 50 – (10,000 years ago) Quaternary extinction, Eurasia Megafauna disappearance

Extinction 51 – (8,200 years ago) The sinking of Doggerland

Extinction 52 – (8,200 years ago) The collapse of Lake Agassiz

Extinction 53 – (8,000 years ago) The flooding of the Persian Gulf basin

Extinction 54 – (7,600 years ago) The Black Sea deluge

Extinction 55 – (4,000 years ago) The dry of the Saharam Forest

 

 

And yet ‘life’ somehow continued and even became more robust and more diverse:

 

“Originations of new groups and rapid diversification (or “radiation”) of certain groups, like Bilateria in the Cambrian, characteristically follow mass extinctions [--]. These rapidly radiating groups may have arisen in the previous geological period, as we now know was the case for Bilateria [--]. There is general agreement that depopulation of existing ecological niches and the creation of new ecological niches by the novel organisms themselves are critical but hard to quantify factors in the dynamics of the appearance of new organisms in the record. Over time, of course, originations have to outnumber extinctions for life to sustain and increase its necessary diversity. There is a long-term increase in the number of taxonomic families visible in the fossil record that extends over multiple mass extinction-origination episodes [--].” [Shapiro (pp. 408-409).]

 

 

But the adaptability of life forms – wherever it comes from – has overcome so many adverse events… and the ability of ‘primitive cells’ to survive and thrive in extreme environments and using ’unusual’ energy sources (e.g. Chernobyl radiation!) makes them so much better than us (lol)…

 

……………………………. …………………..

 

There are more ‘gaps’ in this area of life/biology (some of which are substantial—see quote below), but they only ADD to the ‘level of shock’ of there being a ‘biosphere from nothing’.

 

So, for example, Koonin [pp. 171ff]–

 

“Organisms with large, complex cells are known as eukaryotes—that is, possessing bona fide nuclei. These organisms include the three kingdoms of multicellular life forms, plants, brown algae, and animals, as well as a huge variety of unicellular forms (also known as protists). Eukaryotic cells typically are orders of magnitude bigger than prokaryotic cells and possess complex intracellular organization with diverse membrane-bounded organelles, including the eponymous nucleus and the mitochondria that evolved from endosymbiotic bacteria. Thus, by any reasonable criteria, eukaryotic cells are dramatically more complex than bacteria and archaea. How this complexity evolved is a major enigma of evolutionary biology, ……………………………………………

 

“It is neither practical nor necessary in this book to delve into the innumerable fine details of biological structures. However, to discuss the origin of eukaryotes (hereafter eukaryogenesis) in earnest, we need to fully appreciate the nature and depth of the gulf that separates the cells of eukaryotes from prokaryotic cells. Indeed, there is a sharp divide in the organizational complexity of the cell between eukaryotes and prokaryotes: A typical eukaryotic cell is about a thousand-fold larger by volume than a typical bacterium or archaeon and possesses elaborate intracellular compartmentalization that is not seen even in the most sophisticated prokaryotes.

 

“The compartmentalization of eukaryotic cells relies on an elaborate, diversified endomembrane system and the actin-tubulin-based cytoskeleton. A striking consequence of the intracellular compartmentalization is that eukaryotic cells are physically distinct from the cells of prokaryotes. In prokaryotes, the content of the cell is a solution, even if a viscous one, so macromolecules (proteins and nucleic acids) diffuse more or less freely and reach their cellular destinations through the combination of stochastic movements with trapping in specific complexes. By contrast, in eukaryotes, macromolecules are largely prevented from free diffusion and instead reach their target sites through complex trafficking systems. … Proteins and nucleic acids ooze out of permeabilized bacterial cells, but not (typically) from eukaryotic cells (Hudder, et al., 2003). So the cytosol of eukaryotic cells has much lower entropy than prokaryotic cells—it is hard to think of a more fundamental difference.

 

“ Although the picture of prokaryotic expression regulation is becoming increasingly complex and is now a far cry from the simple Jacob-Monod scheme (see Chapter 5), nothing in prokaryotes can compare with the complexity of the eukaryotic chromatin.

 

“Qualitative distinctions between eukaryotes and prokaryotes are numerous and span various aspects of cell biology, particularly those that are involved with information processing, signal transduction, and intracellular trafficking (see Box 7-1). The organizational complexity of the eukaryotic cells is complemented by extremely sophisticated, cross-talking signaling networks.

 

“No direct counterparts to the signature eukaryotic organelles, genomic features, and functional systems exist in archaea or bacteria. Hence, the very nature of the evolutionary relationships between prokaryotes and eukaryotes becomes a cause of bewilderment. Indeed, sequence comparisons between genome-wide gene sets show beyond doubt that a few thousand eukaryotic genes responsible for key cellular functions (translation, transcription, and replication) share common origins with homologs from archaea and/or bacteria (Koonin, et al., 2004). This evolutionary unity of cellular life forms makes it  an extremely hard and fascinating challenge to explain how largely common components give rise to cells that are so dissimilar in so many respects.

 

But we have to stop here (and do job-hunting), and start on the next shock-factor: the social and community lives of these tiny organisms, and their interactions with OTHER tiny organisms…

 

…………………………

 

The mystery of life seems different than earlier ‘scientific mysteries’. Often the scientist admits that something is ‘poorly understood’ (almost every article abstract contains such a phrase, but the article tries to address it…) but still states the mantra of science’s eventual conquest.

 

I consider Shapiro to be a truly honest man, and even in the midst of ‘confession’ he can hold the line on the juggernaut of science:

 

“In order to be truthful, we must acknowledge that certain questions, like the origins of the first living cells, currently have no credible scientific answers. However, given the historical record of science and technology in achieving the impossible (e.g., space flight, telecommunications, electronic computation, and robotics), there is no reason to believe that unsolved problems will remain without naturalistic explanations indefinitely.” [Shapiro, p. 93]

 

But I am convinced that this area will confound that… as some have already admitted, after decades and decades of work:

 

“As Erica Hayden confessed in the journal Nature, “As sequencing and other new technologies spew forth data,” the complexity unearthed by cell biology “has seemed to grow by orders of magnitude. Delving into it has been like zooming into a Mandelbrot set… that reveals ever more intricate patterns as one peers closer at its boundary.” [Denton, Miracle, p. 16]

 

“The origin of life is the most difficult problem that faces evolutionary biology and, arguably, biology in general. Indeed, the problem is so hard and the current state of the art seems so frustrating that some researchers prefer to dismiss the entire issue as being outside the scientific domain altogether, on the grounds that unique events are not conducive to scientific study.” [Koonin, p. 351]

 

[The quantum substrate of reality may also be in this category, since it is perfectly clear in the mathematics, but generally unclear in everything else.. almost koan-like (“Is the cat dead or alive? No, it quantum-tunneled into some cardboard box.”…lol). And—just to compound ‘unfathomableness’ with more ‘unfathomableness’-- biological organisms USE quantum effects ALLTHE TIME …(e.g. quantum tunneling in enzyme catalysis, olfactory and visual sensing, photosynthesis, magnetoreception, DNA change—the whole field of Quantum Biology…]

 

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It should be starkly obvious by now that this ‘ball of teeming, churning life is odd in the extreme—when compared to the ‘rest of the SOMETHING’—and even more UNEXPECTED as appearing abruptly and without an explanation…

 

In other words,  it makes NO SENSE why it is here, and why it is SO DEMONSTRABLY DIFFERENT from anything else in our experience of the physical cosmos.

 

It is enigmatic in every dimension of its existence and persistence.

 

Its ceaseless churning, and being ‘busy doing stuff’, and ‘acting like it knows what it is doing’ could not have been foreseen, if we were just looking at the miniscule pile of chemicals, or at life-less rocks and oceans…

 

Life sits either [on, under, inside, around, over, enwrapping—or all of the above] a batch of chemicals, and we would NOT have been able to ‘predict’ what that batch of chemicals might become—once it was alive… There are no trendlines, intermediate forms, analogous reactions to suggest that life would show up and that it would be so incredibly sophisticated and competent in its actions and choices.

 

This seems to be another case of ‘something from nothing’ (i.e. unknown causes?)--

 

Like the previous points, it is almost scary to realize that there is NO NATURAL or SCIENTIFIC explanation for its existence, exuberance, or expansiveness.

 

It is just ‘in our face’, challenging us with the obvious intuition/implication of something ‘Outside’ that we might have to face someday in our conscious future…

 

The scary-factor comes from what it might suggest about a putative OUTSIDE-Other…

 

We have already conjectured/suspected that this Outside-Other was an expert mathematician, physicist, cosmologist, logician, and chemist – to me as an emotionally-stunted, socially-immature, OCD-ish, and artistically-monochromed – this is not really threatening from a personality perspective.

 

The power/energy/competence required to CREATE such a SOMETHING is – of course – VERY THREATENING.

 

But this new layer – that of life that acts “like it knows what it is doing” (with types/levels/aspects of cognition at all levels of hierarchy it participates in) and that forces interaction with it—is NOT in my ‘comfort zone’. These things have purpose/goals, and as we move up the taxonomic web, we find things (agents) that look a lot like ME (e.g., domestic pets, service animals) in behavior and aging and even learned habits. They provoke emotions (affections, fear), inspire questions about ethics, and develop loyalty that transcends a reciprocity-only relationship.

 

I know full well of the rapid life-death cycle in them (with predation etc.), but overall, I consider life-as-a-whole to be HEALTHIER than I am…

 

Where this hits me (in this context) can be illustrated by my experiences in darker times in  high school. I wrote literary things for the school newspaper (and won an award for some of them – lol), but I could easily recognize the robustness, health, vivacity of things written by ‘healthier’ people – people I actually ‘feared’ psychologically (for no reasons that came from them—they were always nice to me). They were whole, balanced, comfortable with emotions and uncertainty—I was not… I was defective, less-than-alive, mutated, stunted… without doing ANYTHING, they were a constant reminder (and a painful one) of my desiccated existence… [Many of you readers will have had the same experience, I know…sigh]

 

And when I look NOW at this exuberant and beautiful life-sphere under discussion [like their beautify and wholesome literary works back then], I can sense the ‘wholeness and vivacity’ of whatever sourced it… this OUTSIDE-OTHER now stands apart from me—not only in power, competence, and intelligence (of some kind)—but also in those areas I am NOT such.

 

And so it would be naïve in the extreme for me to presume that any post-mortem encounter with this life-affirming/supporting putative Outside-Other  would invariably be a ‘pleasant experience’ for a disembodied mind (in the post-mortem state). Even if we could confidently infer a ‘love of life’ to an OUTSIDE-OTHER, that might NOT be a good/comforting thing, since such an Outside-Other might hold us accountable for how we TREATED life-forms in our days upon the earth (e.g. some type of judgment or consequences?).

 

Without some self-disclosure, all our estimates of this Outside-other remains speculative—and we have no a-priori reason to believe in something beneficent* (not all expert mathematicians, physicists, and chemists--and universally and continuously ‘beneficent’).

 

[*Strictly speaking, my statement here can be challenged philosophically—on a couple of points, coming up mostly later in the exploration—but those do not carry the evidential force for what we have discussed so far.]

 

 

 

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