The Winding Road from Origin to Emergence (of Life).

Humanity's strive to understand why and how life appeared on planet Earth dates back to prehistoric times. At the beginning of the 19th century, empirical biology started to tackle this question yielding both Charles Darwin's Theory of Evolution and the paradigm that the crucial trigger putting life on its tracks was the appearance of organic molecules. In parallel to these developments in the biological sciences, physics and physical chemistry saw the fundamental laws of thermodynamics being unraveled. Towards the end of the 19th century and during the first half of the 20th century, the tensions between thermodynamics and the "organic-molecules-paradigm" became increasingly difficult to ignore, culminating in Erwin Schrödinger's 1944 formulation of a thermodynamics-compliant vision of life and, consequently, the prerequisites for its appearance. We will first review the major milestones over the last 200 years in the biological and the physical sciences, relevant to making sense of life and its origins and then discuss the more recent reappraisal of the relative importance of metal ions vs. organic molecules in performing the essential processes of a living cell. Based on this reassessment and the modern understanding of biological free energy conversion (aka bioenergetics), we consider that scenarios wherein life emerges from an abiotic chemiosmotic process are both thermodynamics-compliant and the most parsimonious proposed so far.

Methanol on the rocks: green rust transformation promotes the oxidation of methane.

Shared coordination geometries between metal ions within reactive minerals and enzymatic metal cofactors hints at mechanistic and possibly evolutionary homology between particular abiotic chemical mineralogies and biological metabolism. The octahedral coordination of reactive Fe2+/3+ minerals such as green rusts, endemic to anoxic sediments and the early Earth's oceans, mirrors the di-iron reaction centre of soluble methane monooxygenase (sMMO), responsible for methane oxidation in methanotrophy. We show that methane oxidation occurs in tandem with the oxidation of green rust to lepidocrocite and magnetite, mimicking radical-mediated methane oxidation found in sMMO to yield not only methanol but also halogenated hydrocarbons in the presence of seawater. This naturally occurring geochemical pathway for CH4 oxidation elucidates a previously unidentified carbon cycling mechanism in modern and ancient environments and reveals clues into mineral-mediated reactions in the synthesis of organic compounds necessary for the emergence of life.

A self-sustaining serpentinization mega-engine feeds the fougerite nanoengines implicated in the emergence of guided metabolism.

The demonstration by Ivan Barnes et al. that the serpentinization of fresh Alpine-type ultramafic rocks results in the exhalation of hot alkaline fluids is foundational to the submarine alkaline vent theory (AVT) for life's emergence to its 'improbable' thermodynamic state. In AVT, such alkaline fluids ≤ 150°C, bearing H2 > CH4 > HS--generated and driven convectively by a serpentinizing exothermic mega-engine operating in the ultramafic crust-exhale into the iron-rich, CO2> > > NO3--bearing Hadean ocean to result in hydrothermal precipitate mounds comprising macromolecular ferroferric-carbonate oxyhydroxide and minor sulfide. As the nanocrystalline minerals fougerite/green rust and mackinawite (FeS), they compose the spontaneously precipitated inorganic membranes that keep the highly contrasting solutions apart, thereby maintaining redox and pH disequilibria. They do so in the form of fine chimneys and chemical gardens. The same disequilibria drive the reduction of CO2 to HCOO- or CO, and the oxidation of CH4 to a methyl group-the two products reacting to form acetate in a sequence antedating the 'energy-producing' acetyl coenzyme-A pathway. Fougerite is a 2D-layered mineral in which the hydrous interlayers themselves harbor 2D solutions, in effect constricted to ~ 1D by preferentially directed electron hopping/tunneling, and proton Gröthuss 'bucket-brigading' when subject to charge. As a redox-driven nanoengine or peristaltic pump, fougerite forces the ordered reduction of nitrate to ammonium, the amination of pyruvate and oxalate to alanine and glycine, and their condensation to short peptides. In turn, these peptides have the flexibility to sequester the founding inorganic iron oxyhydroxide, sulfide, and pyrophosphate clusters, to produce metal- and phosphate-dosed organic films and cells. As the feed to the hydrothermal mound fails, the only equivalent sustenance on offer to the first autotrophs is the still mildly serpentinizing upper crust beneath. While the conditions here are very much less bountiful, they do offer the similar feed and disequilibria the survivors are accustomed to. Sometime during this transition, a replicating non-ribosomal guidance system is discovered to provide the rules to take on the incrementally changing surroundings. The details of how these replicating apparatuses emerged are the hard problem, but by doing so the progenote archaea and bacteria could begin to colonize what would become the deep biosphere. Indeed, that the anaerobic nitrate-respiring methanotrophic archaea and the deep-branching Acetothermia presently comprise a portion of that microbiome occupying serpentinizing rocks offers circumstantial support for this notion. However, the inescapable, if jarring conclusion is drawn that, absent fougerite/green rust, there would be no structured channelway to life.

Surgical management of Graves' disease: historical context and single institution experience.

AIM: To describe indications and outcomes of total thyroidectomy for Graves' disease in a large New Zealand endocrine surgery unit, and to compare these results to international studies. METHODS: We analysed a prospectively collected database to describe the indications and outcomes of surgery for Graves' disease between December 2001 and January 2021. RESULTS: Among 64 patients who underwent total thyroidectomy at our tertiary centre for Graves' hyperthyroidism, Graves' ophthalmopathy and patient preference/aversion to radioactive iodine were the most common indications for surgery. Total thyroidectomy resulted in long-term control of thyrotoxicosis in all patients. There were no incidences of recurrent laryngeal nerve injury. One patient (1.6%) suffered permanent hypoparathyroidism. CONCLUSION: Total thyroidectomy is a safe and effective treatment for Graves' disease. In our population, total thyroidectomy functions as a second-line treatment for Graves' disease.

Cellular remains in a ~3.42-billion-year-old subseafloor hydrothermal environment.

Subsurface habitats on Earth host an extensive extant biosphere and likely provided one of Earth's earliest microbial habitats. Although the site of life's emergence continues to be debated, evidence of early life provides insights into its early evolution and metabolic affinity. Here, we present the discovery of exceptionally well-preserved, ~3.42-billion-year-old putative filamentous microfossils that inhabited a paleo-subseafloor hydrothermal vein system of the Barberton greenstone belt in South Africa. The filaments colonized the walls of conduits created by low-temperature hydrothermal fluid. Combined with their morphological and chemical characteristics as investigated over a range of scales, they can be considered the oldest methanogens and/or methanotrophs that thrived in an ultramafic volcanic substrate.

The "Water Problem"(sic), the Illusory Pond and Life's Submarine Emergence-A Review.

The assumption that there was a "water problem" at the emergence of life-that the Hadean Ocean was simply too wet and salty for life to have emerged in it-is here subjected to geological and experimental reality checks. The "warm little pond" that would take the place of the submarine alkaline vent theory (AVT), as recently extolled in the journal Nature, flies in the face of decades of geological, microbiological and evolutionary research and reasoning. To the present author, the evidence refuting the warm little pond scheme is overwhelming given the facts that (i) the early Earth was a water world, (ii) its all-enveloping ocean was never less than 4 km deep, (iii) there were no figurative "Icelands" or "Hawaiis", nor even an "Ontong Java" then because (iv) the solidifying magma ocean beneath was still too mushy to support such salient loadings on the oceanic crust. In place of the supposed warm little pond, we offer a well-protected mineral mound precipitated at a submarine alkaline vent as life's womb: in place of lipid membranes, we suggest peptides; we replace poisonous cyanide with ammonium and hydrazine; instead of deleterious radiation we have the appropriate life-giving redox and pH disequilibria; and in place of messy chemistry we offer the potential for life's emergence from the simplest of geochemically available molecules and ions focused at a submarine alkaline vent in the Hadean-specifically within the nano-confined flexible and redox active interlayer walls of the mixed-valent double layer oxyhydroxide mineral, fougerite/green rust comprising much of that mound.

Six 'Must-Have' Minerals for Life's Emergence: Olivine, Pyrrhotite, Bridgmanite, Serpentine, Fougerite and Mackinawite.

Life cannot emerge on a planet or moon without the appropriate electrochemical disequilibria and the minerals that mediate energy-dissipative processes. Here, it is argued that four minerals, olivine ([Mg>Fe]2SiO4), bridgmanite ([Mg,Fe]SiO3), serpentine ([Mg,Fe,]2-3Si2O5[OH)]4), and pyrrhotite (Fe(1-x)S), are an essential requirement in planetary bodies to produce such disequilibria and, thereby, life. Yet only two minerals, fougerite ([Fe2+6xFe3+6(x-1)O12H2(7-3x)]2+·[(CO2-)·3H2O]2-) and mackinawite (Fe[Ni]S), are vital-comprising precipitate membranes-as initial "free energy" conductors and converters of such disequilibria, i.e., as the initiators of a CO2-reducing metabolism. The fact that wet and rocky bodies in the solar system much smaller than Earth or Venus do not reach the internal pressure (≥23 GPa) requirements in their mantles sufficient for producing bridgmanite and, therefore, are too reduced to stabilize and emit CO2-the staple of life-may explain the apparent absence or negligible concentrations of that gas on these bodies, and thereby serves as a constraint in the search for extraterrestrial life. The astrobiological challenge then is to search for worlds that (i) are large enough to generate internal pressures such as to produce bridgmanite or (ii) boast electron acceptors, including imported CO2, from extraterrestrial sources in their hydrospheres.

Chemobrionics: From Self-Assembled Material Architectures to the Origin of Life.

Self-organizing precipitation processes, such as chemical gardens forming biomimetic micro- and nanotubular forms, have the potential to show us new fundamental science to explore, quantify, and understand nonequilibrium physicochemical systems, and shed light on the conditions for life's emergence. The physics and chemistry of these phenomena, due to the assembly of material architectures under a flux of ions, and their exploitation in applications, have recently been termed chemobrionics. Advances in understanding in this area require a combination of expertise in physics, chemistry, mathematical modeling, biology, and nanoengineering, as well as in complex systems and nonlinear and materials sciences, giving rise to this new synergistic discipline of chemobrionics.

Simulating Serpentinization as It Could Apply to the Emergence of Life Using the JPL Hydrothermal Reactor.

The molecules feeding life's emergence are thought to have been provided through the hydrothermal interactions of convecting carbonic ocean waters with minerals comprising the early Hadean oceanic crust. Few laboratory experiments have simulated ancient hydrothermal conditions to test this conjecture. We used the JPL hydrothermal flow reactor to investigate CO2 reduction in simulated ancient alkaline convective systems over 3 days (T = 120°C, P = 100 bar, pH = 11). H2-rich hydrothermal simulant and CO2-rich ocean simulant solutions were periodically driven in 4-h cycles through synthetic mafic and ultramafic substrates and Fe>Ni sulfides. The resulting reductants included micromoles of HS- and formate accompanied possibly by micromoles of acetate and intermittent minor bursts of methane as ascertained by isotopic labeling. The formate concentrations directly correlated with the CO2 input as well as with millimoles of Mg2+ ions, whereas the acetate did not. Also, tens of micromoles of methane were drawn continuously from the reactor materials during what appeared to be the onset of serpentinization. These results support the hypothesis that formate may have been delivered directly to a branch of an emerging acetyl coenzyme-A pathway, thus obviating the need for the very first hydrogenation of CO2 to be made in a hydrothermal mound. Another feed to early metabolism could have been methane, likely mostly leached from primary CH4 present in the original Hadean crust or emanating from the mantle. That a small volume of methane was produced sporadically from the 13CO2-feed, perhaps from transient occlusions, echoes the mixed results and interpretations from other laboratories. As serpentinization and hydrothermal leaching can occur wherever an ocean convects within anhydrous olivine- and sulfide-rich crust, these results may be generalized to other wet rocky planets and moons in our solar system and beyond.

Prospecting for life.

Books with titles like 'The Call of the Wild' seemed to set a path for a life. Thus, I would be an explorer-a plan that did not work out so well, at least at first. On leaving school I got a job as a 'Works Chemist Improver', testing Ni catalysts for the hydrogenation of phenol to cyclohexanol. Taking night classes I passed enough exams to study geology at Queen Mary College, London. Armed thus I travelled to the Solomon Islands where geology is a 'happening'! Next was Canada to visit a mine sunk into a 1.5 billion year old Pb-Zn orebody precipitated from submarine hot springs. At last I reached the Yukon to prospect for silver. Thence to Ireland researching what I also took to be 'exhalative' (i.e. hot spring-related) Pb-Zn orebodies. While there in 1979, the discovery of 350°C metal-bearing acidic waters issuing from submarine Black Smoker chimneys in the Pacific sent us searching for fossil examples in the Irish mines. However, the chimneys we found were more like chemical gardens than Black Smokers, a finding that made us think about the emergence of life. After all, what better for life's emergence than to have a membrane comprising Fe minerals dosed with Ni in our chimneys to mediate the 'hydrogenation' of CO2-life's job anyway. Indeed, such a membrane would keep redox and pH disequilibria at bay, just like biological membranes. At the same time, my field research among Alpine ophiolites-ocean floor mafic rocks obducted to the Alps-indicated that alkaline waters bearing H2 and CH4 were a result of serpentinization, a process that must have operated in all ocean floors over all time. Thus it was that we could predict the Lost City hydrothermal field 10 years before its discovery in the North Atlantic in the year 2000. Lost City comprises a number of alkaline springs at up to 90°C that produce carbonate and brucite (Mg[OH]2) chimneys. We had surmised that Ni-enriched FeS chimneys would have precipitated at comparable alkaline springs issuing into a metal-rich carbonic ocean on the very early Earth (inducing membrane potentials comparable to those capable of succouring all life, and presumably, sufficient to drive life into being). However, our laboratory precipitates also revealed green rust, thought to be the precursor to the magnetite now comprising the Archaean Banded Iron Formations. We now look upon green rust, also known as fougèrite, as the tangible, base fractal of life.

Fougerite: the not so simple progenitor of the first cells.

We here review the extraordinary mineralogical properties of green rusts and their naturally occurring form, fougerite, and discuss the pertinence of these properties within the alkaline hydrothermal vent (AHV) hypothesis for life's emergence. We put forward an extended version of the AHV scenario which enhances the conformity between extant life and its earliest progenitor by extensively making use of fougerite's mechanistic and catalytic particularities.

Redox and pH gradients drive amino acid synthesis in iron oxyhydroxide mineral systems.

Iron oxyhydroxide minerals, known to be chemically reactive and significant for elemental cycling, are thought to have been abundant in early-Earth seawater, sediments, and hydrothermal systems. In the anoxic Fe2+-rich early oceans, these minerals would have been only partially oxidized and thus redox-active, perhaps able to promote prebiotic chemical reactions. We show that pyruvate, a simple organic molecule that can form in hydrothermal systems, can undergo reductive amination in the presence of mixed-valence iron oxyhydroxides to form the amino acid alanine, as well as the reduced product lactate. Furthermore, geochemical gradients of pH, redox, and temperature in iron oxyhydroxide systems affect product selectivity. The maximum yield of alanine was observed when the iron oxyhydroxide mineral contained 1:1 Fe(II):Fe(III), under alkaline conditions, and at moderately warm temperatures. These represent conditions that may be found, for example, in iron-containing sediments near an alkaline hydrothermal vent system. The partially oxidized state of the precipitate was significant in promoting amino acid formation: Purely ferrous hydroxides did not drive reductive amination but instead promoted pyruvate reduction to lactate, and ferric hydroxides did not result in any reaction. Prebiotic chemistry driven by redox-active iron hydroxide minerals on the early Earth would therefore be strongly affected by geochemical gradients of Eh, pH, and temperature, and liquid-phase products would be able to diffuse to other conditions within the sediment column to participate in further reactions.

Green Rust: The Simple Organizing 'Seed' of All Life?

Korenaga and coworkers presented evidence to suggest that the Earth's mantle was dry and water filled the ocean to twice its present volume 4.3 billion years ago. Carbon dioxide was constantly exhaled during the mafic to ultramafic volcanic activity associated with magmatic plumes that produced the thick, dense, and relatively stable oceanic crust. In that setting, two distinct and major types of sub-marine hydrothermal vents were active: ~400 °C acidic springs, whose effluents bore vast quantities of iron into the ocean, and ~120 °C, highly alkaline, and reduced vents exhaling from the cooler, serpentinizing crust some distance from the heads of the plumes. When encountering the alkaline effluents, the iron from the plume head vents precipitated out, forming mounds likely surrounded by voluminous exhalative deposits similar to the banded iron formations known from the Archean. These mounds and the surrounding sediments, comprised micro or nano-crysts of the variable valence FeII/FeIII oxyhydroxide known as green rust. The precipitation of green rust, along with subsidiary iron sulfides and minor concentrations of nickel, cobalt, and molybdenum in the environment at the alkaline springs, may have established both the key bio-syntonic disequilibria and the means to properly make use of them-the elements needed to effect the essential inanimate-to-animate transitions that launched life. Specifically, in the submarine alkaline vent model for the emergence of life, it is first suggested that the redox-flexible green rust micro- and nano-crysts spontaneously precipitated to form barriers to the complete mixing of carbonic ocean and alkaline hydrothermal fluids. These barriers created and maintained steep ionic disequilibria. Second, the hydrous interlayers of green rust acted as engines that were powered by those ionic disequilibria and drove essential endergonic reactions. There, aided by sulfides and trace elements acting as catalytic promoters and electron transfer agents, nitrate could be reduced to ammonia and carbon dioxide to formate, while methane may have been oxidized to methyl and formyl groups. Acetate and higher carboxylic acids could then have been produced from these C1 molecules and aminated to amino acids, and thence oligomerized to offer peptide nests to phosphate and iron sulfides, and secreted to form primitive amyloid-bounded structures, leading conceivably to protocells.

On the Natural History of Flavin-Based Electron Bifurcation.

Electron bifurcation is here described as a special case of the continuum of electron transfer reactions accessible to two-electron redox compounds with redox cooperativity. We argue that electron bifurcation is foremost an electrochemical phenomenon based on (a) strongly inverted redox potentials of the individual redox transitions, (b) a high endergonicity of the first redox transition, and (c) an escapement-type mechanism rendering completion of the first electron transfer contingent on occurrence of the second one. This mechanism is proposed to govern both the traditional quinone-based and the newly discovered flavin-based versions of electron bifurcation. Conserved and variable aspects of the spatial arrangement of electron transfer partners in flavoenzymes are assayed by comparing the presently available 3D structures. A wide sample of flavoenzymes is analyzed with respect to conserved structural modules and three major structural groups are identified which serve as basic frames for the evolutionary construction of a plethora of flavin-containing redox enzymes. We argue that flavin-based and other types of electron bifurcation are of primordial importance to free energy conversion, the quintessential foundation of life, and discuss a plausible evolutionary ancestry of the mechanism.

Frankenstein or a Submarine Alkaline Vent: Who is Responsible for Abiogenesis?: Part 2: As life is now, so it must have been in the beginning.

We argued in Part 1 of this series that because all living systems are extremely far-from-equilibrium dynamic confections of matter, they must necessarily be driven to that state by the conversion of chemically specific external disequilibria into specific internal disequilibria. Such conversions require task-specific macromolecular engines. We here argue that the same is not only true of life at its emergence; it is the enabling cause of that emergence; although here the external driving disequilibria, and the conversion engines needed must have been abiotic. We argue further that the initial step in life's emergence can only create an extremely simple non-equilibrium "seed" from which all the complexity of life must then develop. We assert that this complexity develops incrementally and progressively, each step tested for value added "in flight." And we make the case that only the submarine alkaline hydrothermal vent (AHV) model has the potential to satisfy these requirements.

Frankenstein or a Submarine Alkaline Vent: Who Is Responsible for Abiogenesis?: Part 1: What is life-that it might create itself?

Origin of life models based on "energized assemblages of building blocks" are untenable in principle. This is fundamentally a consequence of the fact that any living system is in a physical state that is extremely far from equilibrium, a condition it must itself build and sustain. This in turn requires that it carries out all of its molecular transformations-obligatorily those that convert, and thereby create, disequilibria-using case-specific mechanochemical macromolecular machines. Mass-action solution chemistry is quite unable to do this. We argue in Part 2 of this series that this inherent dependence of life on disequilibria-converting macromolecular machines is also an obligatory requirement for life at its emergence. Therefore, life must have been launched by the operation of abiotic macromolecular machines driven by abiotic, but specifically "life-like", disequilibria, coopted from mineral precipitates that are chemically and physically active. Models grounded in "chemistry-in-a-bag" ideas, however energized, should not be considered.

Ingested bread clip as an unexpected diagnostic tool.

We describe a case where a bread clip has in fact became lodged adjacent to a portion of small bowel affected by a deposit of previously undiagnosed metastatic serous carcinoma of likely ovarian origin.