The OoL just got less simple?

 

OoL science's top guns did not show up for the showdown ?

 

OoL science's energy problem.

 

Origin of Life science is not a thing?

 

A complex beginning?

 The Elegant Spindle Assembly Checkpoint

Jonathan McLatchie

In a recent article, I discussed the astounding role of motor proteins in eukaryotic cell division. But this is just one of many incredible engineered features associated with mitosis. In this and a subsequent article, I will provide an overview of the elegant molecular mechanisms that underlie the spindle assembly checkpoint and discuss the implications of its dysfunction.

Without this exquisitely engineered system, the cell risks distributing an uneven number of chromosomes to the daughter cells, potentially resulting in cancer or (in the case of meiosis), trisomy conditions such as Down Syndrome (which is characterized by an extra copy of chromosome 21).

Mitotic division (“M phase”) is the culmination of the eukaryotic cell cycle for somatic cells. Mitotic cell division is divided into six phases, illustrated in the figure above. The first is prophase, which is characterized by chromosome condensation (the reorganization of the sister chromatids into compact rod-like structures). Following condensation, assembly of the mitotic spindle apparatus occurs outside the nucleus between the two centrosomes which have duplicated and moved apart to the poles of the cell. 

The second stage of mitosis is prometaphase, which is marked by the disintegration of the nuclear envelope. This is followed by metaphase, where sister chromatids are attached to opposite spindle poles by microtubules bound to protein complexes called kinetochores. In animal cells, 10-40 microtubule-binding sites are associated with any one kinetochore. In yeast, each kinetochore contains only one attachment site. At this point, the chromosomes are seen to be aligned at the cell’s equator (the metaphase plate). The sister chromatids are themselves held together by the protein cohesin.

At anaphase, the sister chromatids separate to form two daughter chromosomes that are pulled towards opposite poles of the spindle. Microtubules bound to kinetochores, as well as the centrosome, are reeled in towards the cell’s periphery by specialized dynein motor proteins that “walk” towards the minus end of the microtubule but are held stationary by cargo-binding domains that are anchored to the cell cortex.

The next phase in the cycle is telophase, the stage at which the daughter chromosomes de-condense at the spindle poles and a new nuclear envelope is assembled. A contractile ring is then formed, marking the final stage of the process — cytokinesis. The contractile ring is comprised of actin and myosin filaments. The cell thus differentiates to form two new daughter cells, each with a nucleus containing a complete and identical set of chromosomes.

The consequences of improper attachment can be catastrophic, with segregation of two chromosome copies to a single daughter cell. The spindle assembly checkpoint pathway is responsible for inhibiting progression of mitosis from metaphase to anaphase until each of the sister chromatids has become correctly bi-oriented and securely associated with the mitotic spindle.

Controlling Metaphase-to-Anaphase Progression

Progression from metaphase to anaphase is mediated by the anaphase promoting complex or cyclosome (APC/C), an E3 ubiquitin ligase. When bound to a protein, Cdc20, the APC functions to ubiquitinate securin (a protein that prevents the cleavage of cohesin by the enzyme separase), as well as the S and M cyclins, thereby targeting them for destruction.1,2,3 The APC/C is phosphorylated by cyclin dependent kinases (Cdks), thus rendering it able to bind to Cdc20 and form the APC/CCdc20 complex. The APC/CCdc20 complex is autoinhibitory, since destruction of Cdks results in a decreased rate of APC/C phosphorylation and, as a consequence, binding of Cdc20.

Microtubule attachment to kinetochores during prometaphase is governed by a “search and capture” mechanism.4,5,6 The property of dynamic instability facilitates the process by which microtubules “search” for kinetochore attachment sites. When a microtubule encounters a kinetochore, the kinetochore is “captured” by means of side-on attachment. The sister chromatids are subsequently positioned at one of the poles of the cell, where more microtubules become attached. After the kinetochore becomes associated with a microtubule from the other pole, the chromosomes move to the equator. Though this process has been viewed for decades as being stochastic, recent work has suggested that it may in fact be more deterministic than previously recognized (see this article for a good discussion).7

This checkpoint pathway relies on a specialized mechanism for monitoring the security of kinetochore-microtubule attachment.8,9 In the case of improper attachment, the kinetochore sends out a signal — the wait anaphase signal — that inhibits activation of APC/CCdc20, thereby arresting metaphase-to-anaphase progression.

Monitoring Spindle-Kinetochore Attachment

The precise mechanism by which the spindle checkpoint system detects improper chromatid biorientation has not been fully elucidated. Two main hypotheses have been proposed, each with its own supporting data.10 One proposal suggests that the system monitors the level of tension at the kinetochore.11,12,13 Another hypothesis is that the system detects attachment of the ends of the microtubules to the kinetochore.14 The spindle assembly checkpoint pathway most likely uses a combination of those two mechanisms.

The importance of tension sensing in the spindle assembly checkpoint was first examined in insect spermatocytes, using a micromanipulation needle to apply tension to an improperly associated chromosome. Tension resulted in the commencement of anaphase in 56 minutes, whereas it was delayed by 5 to 6 hours in the absence of tension.15

Aurora kinase B plays a crucial role in tension sensing, and its inhibition results in an accumulation of improperly attached kinetochores.16,17,18,19,20 Aurora kinase B is believed to induce the inhibitory signal that destabilizes kinetochore-microtubule attachments by phosphorylating components of the kinetochore’s microtubule attachment site, including the mammalian histone-H3 variant centromere protein A (CENP-A) at serine 7.21,22 Aurora kinase B is itself recruited to the centromere by phosphorylation of CENP-A at the same residue by Aurora kinase A.23 When the function of Aurora kinase B is inhibited, one also observes a decrease in concentration of checkpoint components BubR1, Mad2 and CENP-E, and also an inability of BubR1 to rebind to the kinetochore following a decrease in tension at the centromere.24 Aurora kinase B is inactivated only after correct biorientation has occurred.

The role of microtubule attachment is demonstrated by the activity of checkpoint proteins at the kinetochore. For instance, Mad2 is present on unattached kinetochores during prometaphase, but is removed from the kinetochores as they become associated with the spindle.25 Moreover, when mammalian cells are treated with low concentrations of taxol and other microtubule-targeting drugs (thereby removing tension but retaining microtubule-kinetochore attachment), the onset of anaphase is significantly delayed.26,27

A Factory Assembly Line

Eukaryotic cell division is, in many respects, like a factory assembly line, complete with quality-control check points and robotic machines. The sheer number of things that need to go just right for successful division to take place without major complication renders it implausible that such an elegant process could have been produced by a gradual, unguided process. 

By what mechanism is the wait anaphase signal generated? Moreover, how is the spindle assembly checkpoint turned off when proper kinetochore-microtubule attachment has been established? My next article will be taken up with these questions.

Notes

Zachariae, W., Nasmyth, K. (1999) Whose end is destruction: cell division and the anaphase-promoting complex. Genes and Development 13, 2039-2058.

Barford, D. (2011) Structural insights into anaphase-promoting complex function and mechanism. Philosophical Transactions of the Royal Society B. 366, 3605–3624.

Schrock MS, Stromberg BR, Scarberry L, Summers MK. APC/C ubiquitin ligase: Functions and mechanisms in tumorigenesis. Semin Cancer Biol. 2020 Dec;67(Pt 2):80-91.

Kirschner, M., Mitchison, T. (1986) Beyond self-assembly: From microtubules to morphogenesis. Cell 3(9), 329-342.

Biggins S., Murray A.W. (2001) The budding yeast protein kinase Ipl1/ Aurora allows the absence of tension to activate the spindle checkpoint. Genes and Development 15: 3118–3129.

Hauf, S., Watanabe, Y. (2004) Kinetochore orientation in mitosis and meiosis. Cell 119, 317-327.

Soares-de-Oliveira J, Maiato H. Mitosis: Kinetochores determined against random search-and-capture. Curr Biol. 2022 Mar 14;32(5):R231-R234.

Lara-Gonzalez, P., Westhorpe, F.G., Taylor, S.S. (2012) The Spindle Assembly Checkpoint. Current Biology 22, 966-980.

McAinsh AD, Kops GJPL. Principles and dynamics of spindle assembly checkpoint signalling. Nat Rev Mol Cell Biol. 2023 Aug;24(8):543-559.

Pinsky, B.A., Biggins, S. (2005) The spindle checkpoint: tension versus attachment. Trends in Cell Biology 15(9), 486-493.Li, X., Nicklas, B. (1995) Mitotic forces control a cell-cycle checkpoint. Nature 373, 630-632.

Nicklas, R.B., Ward, S.C., Gorbsky, G.J. (1995) Kinetochore Chemistry Is Sensitive to Tension and May Link Mitotic Forces to a Cell Cycle Checkpoint. The Journal of Cell Biology. 130(4), 929-939.

Larson JD, Asbury CL. Relax, Kinetochores Are Exquisitely Sensitive to Tension. Dev Cell. 2019 Apr 8;49(1):5-7.

Waters, J.C., Chen, R., Murray, A.W., Salmon, E.D. (1998) Localization of Mad2 to Kinetochores Depends on Microtubule Attachment, Not Tension. The Journal of Cell Biology 141, 1181-1191.

Li, X., Nicklas, B. (1995) Mitotic forces control a cell-cycle checkpoint. Nature 373, 630-632.

Adams, R.R., Maiato, H., Earnshaw, W.C., Carmena, M. (2001) Essential roles of Drosophila inner centromere protein (INCENP) and Aurora-B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation. Journal of Cell Biology 153, 865-880.

Biggins S., Murray A.W. (2001) The budding yeast protein kinase Ipl1/ Aurora allows the absence of tension to activate the spindle checkpoint. Genes and Development 15: 3118–3129.

Kallio, M.J., McCleland, M.L., Stukenberg, P.T., Gorbsky, G.J. (2002) Inhibition of aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint, and perturbs microtubule dynamics in mitosis. Current Biology 12, 900-905.

Tanaka T.U, Rachidi N., Janke C., Pereira G., Galova M., Schiebel E., Stark M.J., Nasmyth K. (2002) Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 108: 317–329.

Hauf, S., Cole, R.W., LaTerra, S., Zimmer, C., Schnapp, G., Walter, R., Heckel, A., van Meel, J., Rieder, C.L., Peters, J.M. (2003) The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. Journal of Cell Biology 161, 281-294.Zeitlin, S.G., Shelby, R.D., Sullivan, K.F. (2001) CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis. Journal of Cell Biology 155, 1147-1157.

Liu, D., Lampson, M. (2009) Regulation of kinetochore–microtubule attachments by Aurora B kinase. Biochemical Society Transactions 37(5), 976-980.

Kunitoku, N., Sasayama, T., Marumoto, T., Zhang, D., Honda, S., Kobayashi, O., Hatakeyama, K., Ushio, Y., Saya, H., Hirota, T. (2003) CENP-A phosphorylation by Aurora-A in prophase is required for enrichment of Aurora-B at inner centromeres and for kinetochore function. Developmental Cell 5, 853-864.

Ditchfield, C., Johnson, V.L., Tighe, A., Ellston, R., Haworth, C., Johnson, T., Mortlock, A., Keen, N., Taylor, S.S. (2003) Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. Journal of Cell Biology161(2):267-80.

Waters, J.C., Chen, R., Murray, A.W., Salmon, E.D. (1998) Localization of Mad2 to Kinetochores Depends on Microtubule Attachment, Not Tension. The Journal of Cell Biology 141, 1181-1191.

Waters, J.C., Chen, R., Murray, A.W., Salmon, E.D. (1998) Localization of Mad2 to Kinetochores Depends on Microtubule Attachment, Not Tension. The Journal of Cell Biology 141, 1181-1191.

Hoffman, D.B., Pearson, C.G., Yen, T.J., Howell, B.J., Salmon, E.D. (2001) Microtubule-dependent changes in assembly of microtubule motor proteins and mitotic spindle checkpoint proteins at PtK1 kinetochores. Molecular Biology of the Cell 12(7), 1995-2009.

James Tour on why Darwinism's simple beginning was always a nonstarter .

 

Life's beginning just keeps getting less and less simple.

 Study Finds Life’s Origin “Required a Surprisingly Short Interval of Geologic Time”

Casey Luskin

An article at ScienceAlert reports, “Gobsmacking Study Finds Life on Earth Emerged 4.2 Billion Years Ago.” They write, “By studying the genomes of organisms that are alive today, scientists have determined that the last universal common ancestor (LUCA), the first organism that spawned all the life that exists today on Earth, emerged as early as 4.2 billion years ago.” The article then offers an intriguing point about the rapidity with which life appeared on Earth:

Earth, for context, is around 4.5 billion years old. That means life first emerged when the planet was still practically a newborn.

The technical paper in Nature Ecology and Evolution notes that they used not fossil evidence to arrive at such an early date of life on Earth, but molecular clock techniques. The claim that life existed on Earth at 4.2 billion years ago (also noted as “4.2 Ga”) is consistent with some geological evidence (see below), but life at such an early stage is certainly not expected. Some will surely claim that it’s impossible because the heavy bombardment period which frequently saw the Earth sterilized by impacts had not yet concluded. Here’s some of the best early fossil evidence of life on Earth (Ma means “millions of years” ago):

Potential filamentous microfossils from Canada: >3750 – 4280 Ma (Papineau et al., 2022)

Microfossils from Canada: >3770 Ma (Dodd et al., 2017)

δ13C — Excess light carbon: 3.7 Ga. (Rosing, 1999, Ohtomo et al., 2014)

Stromatolites from Greenland: ~3700 Ma (Nutman et al., 2016)

Stromatolites from Western Australia: 3480 Ma (Van Kranendonk et al. 2008, Walter et al., 1980)

As you can see, most of the early fossil evidence of life on Earth is significantly younger than 4.2 Ga, but the possibility of life at 4.2 Ga is allowed by one study. Despite this potential consistency with some fossil evidence, there are multiple reasons to be skeptical of the article’s methods. 

Genetic and Phenotypic Traits

First, it infers the genetic and phenotypic traits of LUCA by assuming that biological similarity always results from common ancestry — and never from common design. This dubious logic is seen in the opening statement from the technical paper which reads, “The common ancestry of all extant cellular life is evidenced by the universal genetic code, machinery for protein synthesis, shared chirality of the almost-universal set of 20 amino acids and use of ATP as a common energy currency.” It’s true that all life uses those components (although the genetic code is not exactly universal), but this does not provide special evidence for common ancestry because the commonality of these similar features could be explained by common design due to their functional utility. After all, the optimization of the genetic code to minimize the effects of mutations upon amino acid sequences has been cited as potential evidence for intelligent design — showing that there could be good reasons for a designer to re-use the standard genetic code across many organisms.

Second, there are fundamental components of life that show great differences across different types of organisms. For example, the mechanisms of DNA replication and cell division in prokaryotes and eukaryotes are highly distinct. Ribosomes in prokaryotes and eukaryotes have fundamental differences, as one paper explains: “Structures of the bacterial ribosome have provided a framework for understanding universal mechanisms of protein synthesis. However, the eukaryotic ribosome is much larger than it is in bacteria, and its activity is fundamentally different in many key ways.” Many other examples could be given.

Third, the paper uses molecular clock methods to date the timing of LUCA, and molecular clock techniques are problematic for many reasons: they’re highly assumption-dependent and notoriously variant, unreliable, and controversial.

Intriguing Implications

All that said, it’s certainly not impossible that life was already present on Earth at 4.2 Ga. And if it were true it would have intriguing implications. As the study concludes:

The result is a picture of a cellular organism that was prokaryote grade rather than progenotic and that probably existed as a component of an ecosystem, using the WLP for acetogenic growth and carbon fixation. … How evolution proceeded from the origin of life to early communities at the time of LUCA remains an open question, but the inferred age of LUCA (~4.2 Ga) compared with the origin of the Earth and Moon suggests that the process required a surprisingly short interval of geologic time.

This suggests that not only did the origin of life occur very soon after the Earth formed but life diversified into a prokaryotic cellular form very soon as well.

The notion that life appeared on Earth shortly after it became habitable is not new. In the past, experts have said just that. For example:

Stephen Jay Gould: “[W]e are left with very little time between the development of suitable conditions for life on the earth’s surface and the origin of life.” (“An Early Start,” Natural History 87 (February, 1978))

Cyril Ponnamperuma: “[W]e are now thinking, in geochemical terms, of instant life…” (Quoted in Fred Hoyle and Chandra Wickramasinghe, Evolution from Space (New York, NY: Simon & Schuster, 1981))

Widespread Life in the Universe?

I don’t think Gould or Ponnamperuma would have anticipated life as early as 4.2 Ga. If such a timeframe is correct, however, it is extraordinary indeed. The ScienceAlert article also gets this point, stating, “This implies that it takes relatively little time for a full ecosystem to emerge … It also demonstrates just how quickly an ecosystem was established on early Earth. This suggests that life may be flourishing on Earth-like biospheres elsewhere in the Universe.” The last point — their punchline about astrobiology and the existence of life elsewhere — of course assumes that life on Earth originated naturally in the first place. It also seems to further assume that, under the right conditions, life originates easily. If it has sprung up early and easily on multiple other planets, according to this naturalist way of thinking, shouldn’t it have sprung up multiple times on Earth, too? And yet universal common ancestry denies that this is so. To all appearances, that’s a conundrum for the naturalist.

But a single origin of terrestrial life has not been established by this study. The most that has been demonstrated is that life appeared early in Earth’s history. Given the difficulties surrounding a natural origin of life, a better inference might be to take this evidence of life’s rapid appearance as evidence that it did NOT arise naturally and required intelligent design.

Predarwinian design vs. Darwinism

 Life Can’t Exist Without Repair Mechanisms, and That’s a Problem for Origin-of-Life Theories

Rob Stadler

A cell is often described as a factory — a quite extraordinary factory that can run autonomously and reproduce itself. The first cell required a lengthy list of components, layers of organization, and a large quantity of complex specified information, as described by previous episodes of Long Story Short. The latest entry in the series emphasizes yet another requirement for life: an abundance of specific repair mechanisms. 

Damage to the “factory” of the cell occurs on two levels: damage to the stored information (either during replication or by natural degradation over time) and damage to the manufacturing machinery (either from faulty production of new machinery or damage incurred during use). Each type of damage requires specific repair mechanisms that demonstrate foresight — the expectation that damage will occur and the ability to recognize, repair and/or recycle only those components that are damaged. All known life requires these mechanisms. 

Damage to Stored Information

The initial process of DNA replication is facilitated by a polymerase enzyme which results in approximately one error for every 10,000 to 100,000 added nucleotides.1 However, no known life can persist with such a high rate of error, if left uncorrected.2 Fortunately, DNA replication in all life includes a subsequent proofreading step — a type of damage repair — that enhances the accuracy by a factor of 100 to 1,000. The current record holder for the sloppiest DNA replication of a living organism, under normal conditions, is Mycoplasma mycoides (and its human-modified relative, JVCI-syn 3A), where only 1 in 33,000,000 nucleotides are incorrectly copied.3

Following the replication of DNA, a daily barrage of DNA damage occurs during normal operating conditions. Life therefore requires sophisticated and highly specific DNA repair mechanisms. In humans, DNA damage response is estimated to involve a hierarchical organization of 605 proteins in 109 assemblies.4 Efforts to make the simplest possible cell by stripping out all non-essential genes has successfully reduced DNA repair to a minimal set of six genes.5 But, these six genes are encoded in thousands of base pairs of DNA, and the machinery to transcribe and translate those genes into the repair enzymes requires a minimum of 149 genes.6 Thus, the DNA code that is required to make DNA repair mechanisms easily exceeds 100,000 base pairs. Here, we encounter a great paradox, first identified in 1971 by Manfred Eigen7: DNA repair is essential to maintain DNA but the genes that code for DNA repair could not have evolved unless the repair mechanisms were already present to protect the DNA. 

Faulty Production of New Machinery

We  used to think that the metabolic machinery in a cell always produced perfect products. But the reality is that faulty products are unavoidable, resulting in the production of interfering or toxic garbage. All living organisms must therefore have machinery that identifies problems and either repairs or recycles the faulty products. 

The cell’s central manufacturing machine is the ribosome, a marvel that produces functional proteins from strands of mRNA (with the help of many supporting molecules). Unfortunately, about 2-4 percent of mRNA strands get stuck in the ribosome during translation into a protein.8 Not only does this halt production, but it could result in production of a toxic, half-finished protein. 

If the mitochondria could not get “unstuck,” life as we know it would end. In the process of self-replication, a single cell must produce an entire library of proteins, placing a heavy burden on the cell’s mitochondria. But with a 2-4 percent rate of stuck mRNA strands, the average cell would have each of its mitochondria get stuck at least five times before the cell could replicate.9 Therefore, life could never replicate and metabolism would cease unless this problem was solved.

Fortunately, all forms of life, even the simplest,9 are capable of trans–translation, typically involving a three-step process. First, a molecule combining transfer and messenger RNA and two helper molecules (SymB and EF-Tu) recognizes that mRNA is stuck in the ribosome and attaches a label to the half-formed protein. This label, called a degron, is essentially a polyalanine peptide. The condemned protein is recognized, degraded, and recycled by one of many proteases. Finally, the mRNA must also be labeled and recycled to keep it from clogging other ribosomes. In some bacteria,10 a pyrophosphohydrolase enzyme modifies the end of the mRNA, labeling it for destruction. An RNAse (another enzyme) then recognizes this label, grabs hold of the mRNA, and draws it close to its magnesium ion, which causes cleavage of the RNA. Another RNAse then finishes the job, breaking the mRNA up into single nucleotides which can be re-used.

The required presence of tools that can destroy proteins and RNA also comes with a requirement that those tools are highly selective. If these tools evolved, one would expect the initial versions to be non-selective, destroying any proteins or RNA within reach, extinguishing life and blocking the process of evolution.11

Note that the set of tools for trans-translation and protein and RNA recycling are all stored in DNA, which must be protected by repair mechanisms. And, these tools cannot be produced without mitochondria, but the mitochondria cannot be unstuck without the action of trans-translation. Thus, we encounter another case of circular causality. 

Damage Incurred During Use

The normal operation of enzymes or metabolites like co-enzymes or cofactors involves chemical reactions that follow specific paths. Deviations from the desired paths can occur from interferences like radiation, oxidative stress, or encountering the wrong “promiscuous” enzyme. These deviations result in rogue molecules that interfere with metabolism or are toxic to the cell. As a result, even the simplest forms of life require several metabolic repair mechanisms: 

“[T]here can be little room left to doubt that metabolite damage and the systems that counter it are mainstream metabolic processes that cannot be separated from life itself.”12

“It is increasingly evident that metabolites suffer various kinds of damage, that such damage happens in all organisms and that cells have dedicated systems for damage repair and containment.”13

As a relatively simple example of a required repair mechanism, even the simplest known cell (JVCI Syn 3A) has to deal with a sticky situation involving sulfur. Several metabolic reactions require molecules with a thiol group — sulfur bonded to hydrogen and to an organic molecule. The organism needs to maintain its thiol groups, but they have an annoying tendency to cross link (i.e., two thiol groups create a disulfide bond, fusing the two molecules together). Constant maintenance is required to break up this undesired linking. Even the simplest known cell requires two proteins (TrxB/JCVISYN3A_0819 and TrxA/JCVISYN3A_0065) to restore thiol groups and maintain metabolism.12 Because the repair proteins are themselves a product of the cell’s metabolism, this creates another path of circular causality: You can’t have prolonged metabolism without the repair mechanisms but you can’t make the repair mechanisms without metabolism.

An Ounce of Prevention is Worth a Pound of Cure

In addition to life’s required repair mechanisms, all forms of life include damage prevention mechanisms. These mechanisms can destroy rogue molecules, stabilize molecules that are prone to going rogue, or guide chemical reactions toward less harmful outcomes. As an example, when DNA is replicated, available monomers of the four canonical nucleotides (G, C, T, and A) are incorporated into the new strand. Some of the cell’s normal metabolites, like dUTP (deoxyuridine triphosphate), are similar to a canonical nucleotide and can be erroneously incorporated into DNA. Even the simplest cell (once again, JVCI-syn3A) includes an enzyme (deoxyuridine triphosphate pyrophosphatase) to hydrolyze dUTP and prevent formation of corrupted DNA.6

Summing Up the Evidence

Those who promote unguided abiogenesis simply brush off all of these required mechanisms, claiming that life started as simplified “proto-cells” that didn’t need repair. But there is no evidence that any form of life could persist or replicate without these repair mechanisms. And the presence of the repair mechanisms invokes several examples of circular causality — quite a conundrum for unintelligent, natural processes alone. Belief that simpler “proto-cells” didn’t require repair mechanisms requires blind faith, set against the prevailing scientific evidence.   

Notes

Babenek A, and Zuizia-Graczyk I. Fidelity of DNA replication — a matter of proofreading. Curr Genet. 2018; 54: 985-996.

Some viruses have high error rates when replicating, but viruses cannot replicate without the help of cellular life, which requires very low error rates. Some specialized DNA polymerases intentionally operate with lower fidelity on a temporary basis for purposes such as antibody diversity. 

Moger-Reischer RZ, et al. Evolution of a Minimal Cell. Nature. 2023; 620: 122-127.

Kratz A, et al. A multi-scale map of protein assemblies in the DNA damage response. Cell Systems 2023; 14: 447-463.

Hutchison CA, et al. Design and synthesis of a minimal bacterial genome. Science 2016; 351: aad6253. 

Breuer M, et al. Essential Metabolism for a Minimal Cell. eLife 2019;8:e36842 DOI: 10.7554/eLife.36842. 

Eigen, M. Self-organization of matter and evolution of biological macromolecules. Naturwissenschaften, 1971; 58: 465–523.

Ito K, et al. Nascentome analysis uncovers futile protein synthesis in Escherichia coli. PLoS One 2011; 6: e28413

Keiler KC, Feaga HA. Resolving nonstop translation complexes is a matter of life or death. Journal of Bacteriology 2014; 196: 2123-2130.

Mackie GA. RNase E: at the interface of bacterial RNA processing and decay. Nature Reviews Microbiology 2013; 11: 45-57.

“Because RNA degradation is ubiquitous in all cells, it is clear that it must be carefully controlled to accurately recognize target RNAs.” Houseley J and Tollervey D. The many pathways of RNA degradation. Cell 2009; 136: 763-776.

Hass D, et al. Metabolite damage and damage control in a minimal genome. American Society for Microbiology 2022; 13: 1-16.

Linster CL, et al. Metabolite damage and its repair or pre-emption. Nature Chemical Biology 2013; 9: 72-80.

For abiogenesis it's not so much uphill as up cliff.

 

James Tour vs. Dave Farina: the view from the centre

 Origin of Life: Cambridge Astrochemist Paul Rimmer Analyzes the Tour-Farina Debate

Brian Miller

Cambridge University astrochemist Paul Rimmer analyzed the debate between James Tour and Dave Farina on the Podcast Capturing Christianity. Rimmer has been recognized as a rising star in the study of the origin of life (OOL). In his charitable and thoughtful demeanor, he represents the antithesis of Farina. He also displays a commitment to describing the science with precision and nuance.

I have many positive thoughts about Rimmer, and I anticipate that many people who watch his post-debate analysis will rightfully come away with a positive view of him. However, the viewer should be aware of a critical caveat: Ultimately, Paul Rimmer is far too credulous about chemical explanations for the origin of life. His stance undoubtedly reflects his membership in the field of mainstream OOL research. To those outside that community, even the research Rimmer lauds as advancing the field only further confirms that life’s originating through natural processes is impossible on scientific grounds.

Analysis of the Debate

Rimmer begins with a helpful tutorial on research into life’s origin. He includes a diagram by John Sutherland on the presumed stages leading to the first self-replicating cell and the current state of the field. Rimmer summarizes the journey toward life as a continuous series of stable systems gradually increasing in complexity until one emerges capable of Darwinian evolution.

Rimmer then expands on specific topics raised by Tour and Farina. He elucidates the research cited by Farina in response to Tour’s question about how the amino acids Asp and Lys could have linked together on the early Earth. Rimmer acknowledges that the articles Farina cited do not directly address Tour’s questions, but he claims they still provide clues as to how amino acid chains could have emerged. He describes how Leman, Orgel, and Ghadiri (2004) linked the amino acids Ala, Phe, Leu, Ser, and Try together with the assistance of carbonyl sulfide. He then describes how Singh et al. (2022) linked aminonitriles (precursors to amino acids) to amino acids by employing catalysts such as thiols.  

Rimmer continues by explaining the research referenced by Farina related to the origin of RNA. During the debate, Tour described how nucleotides often join a growing chain with 2’-5’ linkages instead of the standard 3’-5’ linkages — nucleotides connect at the wrong carbon on the ribose molecule. Farina responded to this hurdle by citing Engelhart et al. (2013) who validated that a nucleotide chain known as a hammerhead ribozyme (RNA enzyme) could still break apart an RNA molecule even if the ribozyme possessed some 2’-5’ linkages. 

Rimmer states that RNA with the wrong linkages could not have been reliably copied, posing a major hurdle to further progress toward life. A single RNA molecule would almost always break apart before it could migrate to the right local environment where it could facilitate a life-relevant reaction. It would have to be copied numerous times before it could play any role in life’s origin. 

Yet Rimmer argues that this challenge is not necessarily insurmountable since Mariani and Sutherland (2017)demonstrated a chemical pathway that replaces 2’-5’ linkages with the correct 3’-5’ linkages. Rimmer acknowledges that this study does not fully solve the problem of building RNA since the correction process is not highly efficient or reliable, but he claims such research provides a “clue” as to how RNA molecules could have emerged. There are additional problems with this research that I will describe below. 

Differing Assumptions

The differing perspectives of Tour and Rimmer result from the differences in their starting assumptions. Rimmer’s scientific education trained him to only consider the possibility that life originated from natural processes. Rimmer tacitly acknowledges this fact in his response to a question about the appearance of design in life. He essentially argues that the origin of life requires “mind” only insofar as chemistry or biology or anything else that happens in nature requires mind. This is consistent with what he has written elsewhere predicting that we will one day find a “complete biological explanation … for the question of how life first originated on Earth.” He states that he does not wish to examine the evidence for design beyond the apparent design behind the laws of physics that allow for life to exist. Consequently, he is not concerned if experiments perfectly match what could have occurred on the early Earth or even if the chemistry is prebiotically plausible.He considers progress as simply finding clues as to what might have occurred. 

In contrast, Tour considers progress in understanding life’s origin as demonstrating a chemical process that could have occurred naturally and could have produced molecules in sufficient abundance and purity to drive the next step toward life. Tour has convincingly argued that no such research exists (see for example here or here).

From Tour’s perspective, a careful analysis of the procedures used in the research Rimmer references (here and here, ) reveals that the studies only moved chemical systems toward life by starting with carefully chosen molecules in concentrations and purities that could never have arisen naturally. The experiments also employed meticulously designed experimental protocols with only marginal similarity to what could have transpired on the ancient Earth. 

If the experiments used more realistic chemical mixtures and environmental conditions, they would not have produced anything biologically relevant. In addition, if the resulting products were deposited in any ancient environment, they would have simply degraded into biologically useless asphalts. Steven Benner describes this tendency as the Asphalt paradox. In other words, this research, while interesting, does not mimic a realistic natural environment, nor does it produce chemical mixtures that could eventually produce life. 

Probability Paradox

The hammerhead ribozyme study cited by Farina and Rimmer poses an additional seemingly insurmountable hurdle to the RNA world hypothesis. Ribozymes with 2’-5’ bonds have primarily been shown to break apart RNA, leading to what Benner refers to as the Probability paradox , which he describes as follows:

Experiments show that RNA molecules that catalyze the destruction of RNA are more likely to arise in a pool of random (with respect to fitness) sequences than RNA molecules that catalyze the replication of RNA, with or without imperfections.

If a system of randomly sequenced RNA had emerged on the early Earth, biologically useful ribozymes would have quickly vanished as the system degraded into simpler molecules. 

Future Presentations

As I noted, Paul Rimmer is thoughtful, civil, and his voice should be heard. He said nothing wrong in his presentation since he was asked to analyze the debate from the perspective of a scientist working in the field of OOL research. But those not working in the field can find many reasons why the research he cites is not persuasive that the chemical origin of life is possible. Perhaps in future discussions, Rimmer could explore how his philosophical framework shapes his interpretation of the results of OOL studies. Ideally, he would also explain why scientists not operating within the same framework assess the state of the field very differently. 

As someone who has also engaged in thoughtful dialogue with OOL researchers, I would be very happy to be part of such a conversation. But I do not want to put Paul Rimmer’s career in any jeopardy: Those working in the field of OOL research would be ill-advised to publicly speak with too much candor about fundamental weaknesses in that field since doing so might jeopardize their career. 

The main event?

 Origin of Life: James Tour and Dave Farina Will Debate at Rice University on Friday; Watch Here

David Klinghoffer 

Everyone’s favorite fake professor, Dave Farina, has devoted many hours on his YouTube Channel, “Professor Dave Explains,” to spewing venom at skeptics of materialist doctrine on biological origins. Perhaps you thought, “Gee, wouldn’t it be interesting if Dave agreed to an in-person debate with, let’s say, Rice University chemist James Tour on the origin of life?”

Dr. Tour is highly skeptical that theorists have got it all figured out about how life arose from non-life on a barren early Earth through known material processes alone. Farina attacked him and his “idiot followers” repeatedly for that. Yeah, Farina is a real mensch, as you may know. Tour, considering that Farina has a YouTube subscriber base of 2.48 million, and thus is reaching a lot of vulnerable people who have no idea how uniformed he is, responded accordingly. In videos of his own, Dr. Tour even offered to fly Farina out to Rice to debate him — put him up at Tour’s home, give him dinner, etc.

<iframe width="460" height="259" src="https://www.youtube.com/embed/qOopv-0BmzY" title="Dr James Tour and Dave Farina Debate Announcement" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen></iframe>

I thought, “Dream on, Professor Tour. ‘Professor Dave’ is never going to take you up on that. At some level he knows what he is.” Guess what? I was wrong. Tomorrow at 7 pm Central (5 pm Pacific), Dave Farina will indeed be debating James Tour at Rice. The topic: “Are We Clueless About the Origin of Life?” That’s Friday, May 19. I trust that Mr. Farina will enjoy his homecooked meal courtesy of the Tour household. What will it be? Meatloaf? Salmon steaks? Don’t forget the first course, a nice bowl of primordial soup fresh from the kitchen. It takes a world-renowned chemist to get that recipe right.

<iframe width="460" height="259" src="https://www.youtube.com/embed/pxEWXGSIpAI" title="Dr. James Tour vs Dave Farina | Are we clueless about the origin of life? #abiogenesis" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen></iframe>

"Professor" Dave gets caught in the crossfire.

Professor Dave vs. James Tour re:the Origin of Life; ringside seat here.