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Saturday, June 15, 2024

Endoplasmic reticulum

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Endoplasmic_reticulum

Cell biology
Animal cell diagram
Components of a typical animal cell: Nucleolus Nucleus Ribosome (dots as part of 5) Vesicle Rough endoplasmic reticulum Golgi apparatus (or, Golgi body) Cytoskeleton Smooth endoplasmic reticulum Mitochondrion Vacuole Cytosol (fluid that contains organelles; with which, comprises cytoplasm) Lysosome Centrosome Cell membrane

The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae (in the RER), and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.

The two types of ER share many of the same proteins and engage in certain common activities such as the synthesis of certain lipids and cholesterol. Different types of cells contain different ratios of the two types of ER depending on the activities of the cell. RER is found mainly toward the nucleus of cell and SER towards the cell membrane or plasma membrane of cell.

The outer (cytosolic) face of the RER is studded with ribosomes that are the sites of protein synthesis. The RER is especially prominent in cells such as hepatocytes. The SER lacks ribosomes and functions in lipid synthesis but not metabolism, the production of steroid hormones, and detoxification. The SER is especially abundant in mammalian liver and gonad cells.

The ER was observed by light microscopy by Garnier in 1897, who coined the term ergastoplasm. The lacy membranes of the endoplasmic reticulum were first seen by electron microscopy in 1945 by Keith R. Porter, Albert Claude, and Ernest F. Fullam. Later, the word reticulum, which means "network", was applied by Porter in 1953 to describe this fabric of membranes.

Structure

The general structure of the endoplasmic reticulum is a network of membranes called cisternae. These sac-like structures are held together by the cytoskeleton. The phospholipid membrane encloses the cisternal space (or lumen), which is continuous with the perinuclear space but separate from the cytosol. The functions of the endoplasmic reticulum can be summarized as the synthesis and export of proteins and membrane lipids, but varies between ER and cell type and cell function. The quantity of both rough and smooth endoplasmic reticulum in a cell can slowly interchange from one type to the other, depending on the changing metabolic activities of the cell. Transformation can include embedding of new proteins in membrane as well as structural changes. Changes in protein content may occur without noticeable structural changes.

Rough endoplasmic reticulum

A 2-minute animation showing how a protein destined for the secretory pathway is synthesized and secreted into the rough endoplasmic reticulum, which appears at the upper right approximately halfway through the animation

The surface of the rough endoplasmic reticulum (often abbreviated RER or rough ER; also called granular endoplasmic reticulum) is studded with protein-manufacturing ribosomes giving it a "rough" appearance (hence its name). The binding site of the ribosome on the rough endoplasmic reticulum is the translocon. However, the ribosomes are not a stable part of this organelle's structure as they are constantly being bound and released from the membrane. A ribosome only binds to the RER once a specific protein-nucleic acid complex forms in the cytosol. This special complex forms when a free ribosome begins translating the mRNA of a protein destined for the secretory pathway. The first 5–30 amino acids polymerized encode a signal peptide, a molecular message that is recognized and bound by a signal recognition particle (SRP). Translation pauses and the ribosome complex binds to the RER translocon where translation continues with the nascent (new) protein forming into the RER lumen and/or membrane. The protein is processed in the ER lumen by an enzyme (a signal peptidase), which removes the signal peptide. Ribosomes at this point may be released back into the cytosol; however, non-translating ribosomes are also known to stay associated with translocons.

The membrane of the rough endoplasmic reticulum is in the form of large double-membrane sheets that are located near, and continuous with, the outer layer of the nuclear envelope. The double membrane sheets are stacked and connected through several right- or left-handed helical ramps, the "Terasaki ramps", giving rise to a structure resembling a parking garage. Although there is no continuous membrane between the endoplasmic reticulum and the Golgi apparatus, membrane-bound transport vesicles shuttle proteins between these two compartments. Vesicles are surrounded by coating proteins called COPI and COPII. COPII targets vesicles to the Golgi apparatus and COPI marks them to be brought back to the rough endoplasmic reticulum. The rough endoplasmic reticulum works in concert with the Golgi complex to target new proteins to their proper destinations. The second method of transport out of the endoplasmic reticulum involves areas called membrane contact sites, where the membranes of the endoplasmic reticulum and other organelles are held closely together, allowing the transfer of lipids and other small molecules.

The rough endoplasmic reticulum is key in multiple functions:

Manufacture of lysosomal enzymes with a mannose-6-phosphate marker added in the cis-Golgi network.
Manufacture of secreted proteins, either secreted constitutively with no tag or secreted in a regulatory manner involving clathrin and paired basic amino acids in the signal peptide.
Integral membrane proteins that stay embedded in the membrane as vesicles exit and bind to new membranes. Rab proteins are key in targeting the membrane; SNAP and SNARE proteins are key in the fusion event.
Initial glycosylation as assembly continues. This is N-linked (O-linking occurs in the Golgi).
- N-linked glycosylation: If the protein is properly folded, oligosaccharyltransferase recognizes the AA sequence NXS or NXT (with the S/T residue phosphorylated) and adds a 14-sugar backbone (2-N-acetylglucosamine, 9-branching mannose, and 3-glucose at the end) to the side-chain nitrogen of Asn.

Smooth endoplasmic reticulum

In most cells the smooth endoplasmic reticulum (abbreviated SER) is scarce. Instead there are areas where the ER is partly smooth and partly rough, this area is called the transitional ER. The transitional ER gets its name because it contains ER exit sites. These are areas where the transport vesicles which contain lipids and proteins made in the ER, detach from the ER and start moving to the Golgi apparatus. Specialized cells can have a lot of smooth endoplasmic reticulum and in these cells the smooth ER has many functions. It synthesizes lipids, phospholipids, and steroids. Cells which secrete these products, such as those in the testes, ovaries, and sebaceous glands have an abundance of smooth endoplasmic reticulum. It also carries out the metabolism of carbohydrates, detoxification of natural metabolism products and of alcohol and drugs, attachment of receptors on cell membrane proteins, and steroid metabolism. In muscle cells, it regulates calcium ion concentration. Smooth endoplasmic reticulum is found in a variety of cell types (both animal and plant), and it serves different functions in each. The smooth endoplasmic reticulum also contains the enzyme glucose-6-phosphatase, which converts glucose-6-phosphate to glucose, a step in gluconeogenesis. It is connected to the nuclear envelope and consists of tubules that are located near the cell periphery. These tubes sometimes branch forming a network that is reticular in appearance. In some cells, there are dilated areas like the sacs of rough endoplasmic reticulum. The network of smooth endoplasmic reticulum allows for an increased surface area to be devoted to the action or storage of key enzymes and the products of these enzymes.

Sarcoplasmic reticulum

The sarcoplasmic reticulum (SR), from the Greek σάρξ sarx ("flesh"), is smooth ER found in muscle cells. The only structural difference between this organelle and the smooth endoplasmic reticulum is the composition of proteins they have, both bound to their membranes and drifting within the confines of their lumens. This fundamental difference is indicative of their functions: The endoplasmic reticulum synthesizes molecules, while the sarcoplasmic reticulum stores calcium ions and pumps them out into the sarcoplasm when the muscle fiber is stimulated. After their release from the sarcoplasmic reticulum, calcium ions interact with contractile proteins that utilize ATP to shorten the muscle fiber. The sarcoplasmic reticulum plays a major role in excitation-contraction coupling.

Functions

The endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs called cisternae and the transport of synthesized proteins in vesicles to the Golgi apparatus. Rough endoplasmic reticulum is also involved in protein synthesis. Correct folding of newly made proteins is made possible by several endoplasmic reticulum chaperone proteins, including protein disulfide isomerase (PDI), ERp29, the Hsp70 family member BiP/Grp78, calnexin, calreticulin, and the peptidylprolyl isomerase family. Only properly folded proteins are transported from the rough ER to the Golgi apparatus – unfolded proteins cause an unfolded protein response as a stress response in the ER. Disturbances in redox regulation, calcium regulation, glucose deprivation, and viral infection or the over-expression of proteins can lead to endoplasmic reticulum stress response (ER stress), a state in which the folding of proteins slows, leading to an increase in unfolded proteins. This stress is emerging as a potential cause of damage in hypoxia/ischemia, insulin resistance, and other disorders.

Protein transport

Secretory proteins, mostly glycoproteins, are moved across the endoplasmic reticulum membrane. Proteins that are transported by the endoplasmic reticulum throughout the cell are marked with an address tag called a signal sequence. The N-terminus (one end) of a polypeptide chain (i.e., a protein) contains a few amino acids that work as an address tag, which are removed when the polypeptide reaches its destination. Nascent peptides reach the ER via the translocon, a membrane-embedded multiprotein complex. Proteins that are destined for places outside the endoplasmic reticulum are packed into transport vesicles and moved along the cytoskeleton toward their destination. In human fibroblasts, the ER is always co-distributed with microtubules and the depolymerisation of the latter cause its co-aggregation with mitochondria, which are also associated with the ER.

The endoplasmic reticulum is also part of a protein sorting pathway. It is, in essence, the transportation system of the eukaryotic cell. The majority of its resident proteins are retained within it through a retention motif. This motif is composed of four amino acids at the end of the protein sequence. The most common retention sequences are KDEL for lumen-located proteins and KKXX for transmembrane proteins. However, variations of KDEL and KKXX do occur, and other sequences can also give rise to endoplasmic reticulum retention. It is not known whether such variation can lead to sub-ER localizations. There are three KDEL (1, 2 and 3) receptors in mammalian cells, and they have a very high degree of sequence identity. The functional differences between these receptors remain to be established.

Bioenergetics regulation of ER ATP supply by a CaATiER mechanism

The endoplasmic reticulum does not harbor an ATP-regeneration machinery, and therefore requires ATP import from mitochondria. The imported ATP is vital for the ER to carry out its house keeping cellular functions, such as for protein folding and trafficking.

The ER ATP transporter, SLC35B1/AXER, was recently cloned and characterized, and the mitochondria supply ATP to the ER through a Ca²⁺-antagonized transport into the ER (CaATiER) mechanism. The CaATiER mechanism shows sensitivity to cytosolic Ca²⁺ ranging from high nM to low μM range, with the Ca²⁺-sensing element yet to be identified and validated.

Clinical significance

Increased and supraphysiological ER stress in pancreatic β cells disrupts normal insulin secretion, leading to hyperinsulinemia and consequently peripheral insulin resistance associated with obesity in humans. Human clinical trials also suggested a causal link between obesity-induced increase in insulin secretion and peripheral insulin resistance.

Abnormalities in XBP1 lead to a heightened endoplasmic reticulum stress response and subsequently causes a higher susceptibility for inflammatory processes that may even contribute to Alzheimer's disease. In the colon, XBP1 anomalies have been linked to the inflammatory bowel diseases including Crohn's disease.

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum. The UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. The UPR functions to restore normal function of the cell by halting protein translation, degrading misfolded proteins, and activating the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. Sustained overactivation of the UPR has been implicated in prion diseases as well as several other neurodegenerative diseases and the inhibition of the UPR could become a treatment for those diseases.

Immuno-psychiatry

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Immuno-psychiatry

Immuno-psychiatry, according to Pariante, is a discipline that studies the connection between the brain and the immune system. It differs from psychoneuroimmunology by postulating that behaviors and emotions are governed by peripheral immune mechanisms. Depression, for instance, is seen as malfunctioning of the immune system.

History

History Tying The Immune System to Psychosis

Since the late 1800’s scientists and physicians have noticed a possible link between the immune system and psychiatric disorders. In 1876 Alexandar Rosenblum, and later in the 1880s Dr. Julius Wagner-Jauregg, observe patients with neurosyphilis, syphilis that had spread to the nervous system, have decreased symptoms of psychosis after contracting malaria. Then from the 1920s, Karl Menninger notices how many patients recovering or recovered from influenza have psychosis similar to that seen in patients with schizophrenia. Moritz Tramer then reports how schizophrenia is associated with a child being born in the winter or spring months (when influenza is most commonly contracted). Later in 1980s, much research is conducted associating increased rates of schizophrenia in patients with a history of prenatal, postnatal infection, and especially childhood central nervous system infections.

History: Tying Inflammatory States to Changes in Mood

William Osler in the 1890s observed that when animals are sick, they became sleepy, depressed, less active, and generally with a lower appetite. Then in the 1890s, investigation into the similarity in these animal “sick behavior” and persons with depression led to more and more studies showing elevated levels of pro-inflammatory cytokines among persons with depression. Many of these early studies in sickness behavior showed significant differences in the many pro-inflammatory cytokines reviving interest into the role that the immune system played in psychiatric disorders.

Modern immuno-psychiatry model

Modern immuno-psychiatry theory now focuses on some variation of this model of how the environment leads to biological changes which affect the peripheral immune system and later affect the mind, mood, behavior, and response to psychiatric treatment. Stress leads to processing by the sympathetic nervous system which releases catecholamines (dopamine and norepinephrine) that increase the number of monocytes, which respond to inflammatory signals (DAMPS/MAMPs), which causes the release of pro-inflammatory cytokines, which then later reach the brain and lead to changes in neurotransmitter metabolism neuronal signaling, and ultimately behavior.

Support For The Role of The Immune System Affecting Mood and Behavior

How Cytokines Can Reach The Brain And Central Nervous System

Passing through more leaky areas of the blood brain barrier, near the circumventricular organs.
Active transport of cytokines in the blood to bypass the Blood Brain Barrier.
Activation of endothelial cells lining the brain's vasculature which later release cytokines into the central nervous system.
Cytokines binding receptors on peripheral afferent nerves which then conduct a message to the central nervous system in specialized regions of the brain which release their own cytokines.
Recruitment of monocytes in the blood which then travel to the brain and release cytokines.

How Cytokines Can Cause Changes To Neurotransmitter levels Which Can Sometimes Be Reversed.

Pro-inflammatory cytokines alter the metabolism of neurotransmitters and has been documented to effect decrease levels of serotonin, increase indolamine-2,3-dioxygenase (IDO) activity(which normally catabolizes tryptophan and consequentially decrease serotonin synthesis), increased levels of kynurenine (leading to decreased glutamate and dopamine release), decrease dopamine as well as decreased levels of expression of tyrosine hydroxylase (which is required to make dopamine), increased levels of quinolinic acid, leading to more NMDA receptor activation and oxidative stress leading to excitotoxicity and neurodegeneration.

Additionally, cytokines interferon-alpha and IL-6 can cause reversible reductions in brain levels of tetrahydrobiopterin (used in the serotonin, dopamine, and norepinephrine synthesis pathways). However, inhibition of nitric oxide synthase, one of the down stream effects of interferon-alpha, can lead to a reversal of this decrease in tetrahydrobiopterin.

How Cytokines Can Cause Molecular And Cellular Changes Similar to Those Seen In Patients With Mood Disorders

Microglia make the most cytokines of all cells in the brain, respond to stress, and are likely important in the stress response as they are found to be increased in density (yet decreased in overall number) in different parts of the brain of persons who had killed themselves with major depressive disorder, bipolar disorder, and schizophrenia.

On a molecular level, cytokines effect the glutamate metabolism of the nervous system and can lead to structural changes involving microglia similar to those seen in depressed patients. TNF-alpha and IL-1, through oxidative stress via increased release of reactive oxygen and nitrogen species, impair re-uptake and transport of glutamate by glial cells, increasing release of glutamate by astrocytes and microglia, leading to an excitotoxic state. This loss of oligodendrocytes (the astrocytes and microglia mentioned before) are a key marker in structural analysis of the brains of depressed patient populations.

How Inflammatory Cytokines Can Disrupt Cortisol Signaling And The HPA-axis Seen in Psychopathologies

The hippocampus helps regulate the HPA-axis' secretion of cortisol and has the largest number of glucocorticoid receptors in the brain. This makes it making it especially sensitive to stress and stress related increases to cortisol. Additionally, the neuroendocrine response by the HPA-axis is effected by the regulation of glucocorticoid receptor expression in the different regions of the brain. And multiple studies have shown that “altered HPA stress responsivity being associated with increased risk of psychopathology” such as in the study of human brain cell, gathered post-mortem, mRNA was harvested in patients who had killed themselves with either a history or a lack of a history of early childhood stresses revealed significant epigenetic changes in glucocorticoid receptor expression.

Patients with elevated levels chronic inflammatory cytokines, (such as those with chronic hepatitis C and others undergoing injections of interferon-alpha, cause changes in glucocorticoid receptors and cortisol release similar to patients with major depression. Both exhibit a loss of the normal cortisol rhythm of secretion throughout the day, and both show a loss of functional glucocorticoid receptors which would otherwise decrease the inflammation in the body.

Associated findings in Major Depressive Disorder

Following studies of patients with significant chronic inflammation, like those undergoing interferon-alpha therapy for hepatitis C showing an association with depressive symptoms, not unlike Osler's "sickness behavior", more studies into major depressive disorder and its link to inflammation have been done. There have been many studies inferring a link between inflammation and major depressive disorder from correlating levels of cytokines in the blood, correlating genes linked to inflammation to treatment response, and changes in cytokines to antidepressant therapy.

Many studies investigating the role of the immune system in patients with major depressive disorder found that such patients had decreased immune cell activity of natural killer cells and lymphocytes despite reliably having elevated levels of pro-inflammatory cytokines(IL-6, TNF-alpha, and C-reactive protein). Depression is also associated with a decreasein regulatory T cells which secrete anti-inflammatory IL-10 and TGF-beta. Different studies have shown the that persons with depression also have lower circulating levels of IL-10, TGF-beta, in addition to the mentioned elevated levels of pro-inflammatory IL-6 in their blood stream.

Antidepressants have been used to infer a link between inflammation and major depressive disorder. In human studies associating the link between inflammation and depression found that giving antidepressants prior to an expected inflammatory insult decreased observed severity of depression. For example, giving paroxetine prior to treatment for malignant melanoma and hepatitis C was found to decrease depressive symptoms compared to persons not given paroxetine (an antidepressant). Additional experimental support of giving an antidepressant prior to injection of endotoxin, a substance known to cause systemic inflammation) was also found to reduce self-reported symptoms of depression. In studies of antidepressant use, some persons show return to normal cytokine levels with depression treatment. Patients with major depressive disorder treated with antidepressants have an increase in regulatory T cells and a decrease in inflammatory IL-1 beta. And even more strongly replicated, patients with increased levels of pro-inflammatory cytokines, or even genes tied to increased pro-inflammatory activity, are more likely to have antidepressant resistant depression.

Through all these studies there seems to be a slight difference in symptoms of major depressive disorder with and without inflammation. Inflammation related depression tends to have less guilt/self negativity and increased slowness and lack of appetite compared to depression in persons without increased levels of systemic inflammation.

Proposed roles of the immune system in Schizophrenia and Psychotic Disorders

There are ties to episodes of psychosis, and persons at risk for schizophrenia, severity of schizophrenia, and with antipsychotic therapy especially with levels of IL-6 in the blood as well as the cerebrospinal fluid of patients with schizophrenia.

Following studies revealing kynurenic acid's uniqueness as being the NMDA receptor's only endogenous (naturally found in the body) antagonist, and the fact that psychosis can be elicited from NMDA receptor antagonism, multiple studies investigated and confirmed change levels of this kynurenic acid may be related to psychosis. Later drug studies have found that COX1 inhibition, which increases kynurenic acid, has been reported to cause psychotic symptoms. COX2 selective inhibitors like celecoxib, which reduce kynurenic acid, were found to reduce clinical severity of schizophrenia in non-randomized, unblinded clinical trials. While encouraging, these results remain to be confirmed in randomized clinical trials with confirmatory results before they are even considered for off-label usage.

Overall impact for clinical medicine

The overall results for the many clinical trials of combinations of NSAIDS and antidepressants, proposed to more thoroughly treat standard major depressive disorder and treatment-resistant major depressive disorder, shows that the current degree of importance of addressing the inflammatory component of mood disorders is unclear. Mixed results of some or no improvement in such studies, and the relative lack of studies recruiting sufficient numbers of patients with treatment resistant depression, a lack of studies of patients with chronic inflammation and treatment depression, and a lack of a standardized definition of an elevated chronic inflammatory state leaves more studies to be desired in pursuing the understanding of inflammation and psychiatric disorders.

Alternative abiogenesis scenarios

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Alternative_abiogenesis_scenarios

A scenario is a set of related concepts pertinent to the origin of life (abiogenesis), such as the iron-sulfur world. Many alternative abiogenesis scenarios have been proposed by scientists in a variety of fields from the 1950s onwards in an attempt to explain how the complex mechanisms of life could have come into existence. These include hypothesized ancient environments that might have been favourable for the origin of life, and possible biochemical mechanisms.

A scenario

The biochemist Nick Lane has proposed a possible scenario for the origin of life that integrates much of the available evidence from biochemistry, geology, phylogeny, and experimentation:

Iron-Sulphur minerals like Greigite catalyse the reduction of carbon dioxide in hydrothermal vents to make Krebs cycle intermediates.
Protocells in contact with a thin rock barrier in a hydrothermal vent get a free supply of energy from the pH gradient.
Protocells in a hydrothermal vent can grow by adding fatty acids to their membrane, other organics to their cytoplasm.
Nucleotides in a protocell in a hydrothermal vent can polymerise into random strings of RNA. Any that have even slight catalytic activity will favour the growth and replication of their protocells, a start to natural selection.
A protocell away from a hydrothermal vent must create its own proton-motive force, such as by splitting hydrogen sulphide.
Ferredoxin catalyses the splitting of hydrogen sulphide, its earliest repeating amino acid sequence perhaps coded for by an incomplete genetic code.
Anoxygenic photosynthesis, using hydrogen sulphide, ended the need for scarce hydrogen.
Early heterotrophs used Krebs cycle respiration; then oxygenic photosynthesis gave full independence of volcanic energy.

Environments

Many environments have been proposed for the origin of life.

Fluctuating salinity: dilute and dry-down

Harold Blum noted in 1957 that if proto-nucleic acid chains spontaneously form duplex structures, then there is no way to dissociate them.

The Oparin-Haldane hypothesis addresses the formation, but not the dissociation, of nucleic acid polymers and duplexes. However, nucleic acids are unusual because, in the absence of counterions (low salt) to neutralize the high charges on opposing phosphate groups, the nucleic acid duplex dissociates into single chains. Early tides, driven by a close moon, could have generated rapid cycles of dilution (high tide, low salt) and concentration (dry-down at low tide, high salt) that exclusively promoted the replication of nucleic acids through a process dubbed tidal chain reaction (TCR). This theory has been criticized on the grounds that early tides may not have been so rapid, although regression from current values requires an Earth–Moon juxtaposition at around two Ga, for which there is no evidence, and early tides may have been approximately every seven hours. Another critique is that only 2–3% of the Earth's crust may have been exposed above the sea until late in terrestrial evolution.

The tidal chain reaction theory has mechanistic advantages over thermal association/dissociation at deep-sea vents because it requires that chain assembly (template-driven polymerization) takes place during the dry-down phase, when precursors are most concentrated, whereas thermal cycling needs polymerization to take place during the cold phase, when the rate of chain assembly is lowest and precursors are likely to be more dilute.

Hot freshwater lakes

Jack W. Szostak suggested that geothermal activity provides greater opportunities for the origination of life in open lakes where there is a buildup of minerals. In 2010, based on spectral analysis of sea and hot mineral water, Ignat Ignatov and Oleg Mosin demonstrated that life may have predominantly originated in hot mineral water. Hot mineral water that contains hydrogen carbonate and calcium ions has the most optimal range. This case is similar to the origin of life in hydrothermal vents, but with hydrogen carbonate and calcium ions in hot water. At a pH of 9–11, the reactions can take place in seawater. According to Melvin Calvin, certain reactions of condensation-dehydration of amino acids and nucleotides in individual blocks of peptides and nucleic acids can take place in the primary hydrosphere with pH 9–11 at a later evolutionary stage. Some of these compounds like hydrocyanic acid (HCN) have been proven in the experiments of Miller. This is the environment in which the stromatolites have been created. David Ward described the formation of stromatolites in hot mineral water at the Yellowstone National Park. In 2011, Tadashi Sugawara created a protocell in hot water.

Geothermal springs

Bruce Damer and David Deamer argue that cell membranes cannot be formed in salty seawater, and must therefore have originated in freshwater environments like pools replenished by a combination of geothermal springs and rainfall. Before the continents formed, the only dry land on Earth would be volcanic islands, where rainwater would form ponds where lipids could form the first stages towards cell membranes. During multiple wet-dry cycles, biopolymers would be synthesized and are encapsulated in vesicles after condensation. Zinc sulfide and manganese sulfide in these ponds would have catalyzed organic compounds by abiotic photosynthesis. Experimental research at geothermal springs successfully synthesized polymers and were encapsulated in vesicles after exposure to UV light and multiple wet-dry cycles. At temperatures of 60 to 80 °C at geothermal fields, biochemical reactions can occur. These predecessors of true cells are assumed to have behaved more like a superorganism rather than individual structures, where the porous membranes would house molecules which would leak out and enter other protocells. Only when true cells had evolved would they gradually adapt to saltier environments and enter the ocean.

6 of the 11 biochemical reactions of the rTCA cycle can occur in hot metal-rich acidic water which suggests metabolic reactions might have originated in this environment, this is consistent with the enhanced stability of RNA phosphodiester, aminoacyl-tRNA bonds, and peptides in acidic conditions. Cycling between supercritical and subcritical CO₂ at tectonic fault zones might have led to peptides integrating with and stabilizing lipid membranes. This is suggested to have driven membrane protein evolution, as it shown that a selected peptide (H-Lys-Ser-Pro-Phe-Pro-Phe-Ala-Ala-OH) causes the increase of membrane permeability to water. David Deamer and Bruce Damer states that the prebiotic chemistry does not require ultraviolet irradiation as the chemistry could also have occurred under shaded areas that protected biomolecules from photolysis.

Deep sea alkaline vents

Nick Lane believes that no known life forms could have utilized zinc-sulfide based photosynthesis, lightning, volcanic pyrite synthesis, or UV radiation as a source of energy. Rather, he instead suggests that deep sea alkaline vents is more likely to have been a source energy for early cellular life. Serpentinization at alkaline hydrothermal vents produce methane and ammonia. Mineral particles that have similar properties to enzymes at deep sea vents would catalyze organic compounds out of dissolved CO₂ within seawater. Porous rock might have promoted condensation reactions of biopolymers and act as a compartment of membranous structures, however it is unknown about how it could promote coding and metabolism. Acetyl phosphate, which is readily synthesized from thioacetate, can promote aggregation of adenosine monophosphate of up to 7 monomers which is considered energetically favored in water due to interactions between nucleobases. Acetyl phosphate can stabilize aggregation of nucleotides in the presence of Na⁺ and could possibly promote polymerization at mineral surfaces or lower water activity. An external proton gradient within a membrane would have been maintained between the acidic ocean and alkaline seawater. The descendants of the last universal common ancestor, bacteria and archaea, were probably methanogens and acetogens. The earliest microfossils, dated to be 4.28 to 3.77 Ga, were found at hydrothermal vent precipitates. These microfossils suggest that early cellular life began at deep sea hydrothermal vents. Exergonic reactions at these environments could have provided free energy that promoted chemical reactions conducive to prebiotic biomolecules.

Nonenzymatic reactions of glycolysis and the pentose phosphate pathway can occur in the presence of ferrous iron at 70 °C, the reactions produce erythrose 4-phosphate, an amino acid precursor and ribose 5-phosphate, a nucleotide precursor. Pyrimidines are shown to be synthesized from the reaction between aspartate and carbamoyl phosphate at 60 °C and in the presence of metals, it is suggested that purines could be synthesized from the catalysis of metals. Adenosine monophosphate are also shown to be synthesized from adenine, monopotassium phosphate or pyrophosphate, and ribose at silica at 70 °C. Reductive amination and transamination reactions catalyzed by alkaline hydrothermal vent mineral and metal ions produce amino acids. Long chain fatty acids can be derived from formic acid or oxalic acid during Fischer-Tropsch-type synthesis. Carbohydrates containing an isoprene skeleton can be synthesized from the formose reaction. Isoprenoids incorporated into fatty acid vesicles can stabilize the vesicles, which are suggested to have driven the divergence of bacterial and archaeal lipids.

Volcanic ash in the ocean

Geoffrey W. Hoffmann has argued that a complex nucleation event as the origin of life involving both polypeptides and nucleic acid is compatible with the time and space available in the primary oceans of Earth. Hoffmann suggests that volcanic ash may provide the many random shapes needed in the postulated complex nucleation event. This aspect of the theory can be tested experimentally.

Gold's deep-hot biosphere

In the 1970s, Thomas Gold proposed the theory that life first developed not on the surface of the Earth, but several kilometers below the surface. It is claimed that the discovery of microbial life below the surface of another body in our Solar System would lend significant credence to this theory.

Radioactive beach hypothesis

Zachary Adam claims that tidal processes that occurred during a time when the Moon was much closer may have concentrated grains of uranium and other radioactive elements at the high-water mark on primordial beaches, where they may have been responsible for generating life's building blocks. According to computer models, a deposit of such radioactive materials could show the same self-sustaining nuclear reaction as that found in the Oklo uranium ore seam in Gabon. Such radioactive beach sand might have provided sufficient energy to generate organic molecules, such as amino acids and sugars from acetonitrile in water. Radioactive monazite material also has released soluble phosphate into the regions between sand-grains, making it biologically "accessible." Thus amino acids, sugars, and soluble phosphates might have been produced simultaneously, according to Adam. Radioactive actinides, left behind in some concentration by the reaction, might have formed part of organometallic complexes. These complexes could have been important early catalysts to living processes.

John Parnell has suggested that such a process could provide part of the "crucible of life" in the early stages of any early wet rocky planet, so long as the planet is large enough to have generated a system of plate tectonics which brings radioactive minerals to the surface. As the early Earth is thought to have had many smaller plates, it might have provided a suitable environment for such processes.

The hypercycle

In the early 1970s, Manfred Eigen and Peter Schuster examined the transient stages between the molecular chaos and a self-replicating hypercycle in a prebiotic soup. In a hypercycle, the information storing system (possibly RNA) produces an enzyme, which catalyzes the formation of another information system, in sequence until the product of the last aids in the formation of the first information system. Mathematically treated, hypercycles could create quasispecies, which through natural selection entered into a form of Darwinian evolution. A boost to hypercycle theory was the discovery of ribozymes capable of catalyzing their own chemical reactions. The hypercycle theory requires the existence of complex biochemicals, such as nucleotides, which do not form under the conditions proposed by the Miller–Urey experiment.

Iron–sulfur world

In the 1980s, Wächtershäuser and Karl Popper postulated the iron–sulfur world hypothesis for the evolution of pre-biotic chemical pathways. It traces today's biochemistry to primordial reactions which synthesize organic building blocks from gases. Wächtershäuser systems have a built-in source of energy: iron sulfides such as pyrite. The energy released by oxidising these metal sulfides can support synthesis of organic molecules. Such systems may have evolved into autocatalytic sets constituting self-replicating, metabolically active entities predating modern life forms. Experiments with sulfides in an aqueous environment at 100 °C produced a small yield of dipeptides (0.4% to 12.4%) and a smaller yield of tripeptides (0.10%). However, under the same conditions, dipeptides were quickly broken down.

Several models postulate a primitive metabolism, allowing RNA replication to emerge later. The centrality of the Krebs cycle (citric acid cycle) to energy production in aerobic organisms, and in drawing in carbon dioxide and hydrogen ions in biosynthesis of complex organic chemicals, suggests that it was one of the first parts of the metabolism to evolve. Concordantly, geochemists Szostak and Kate Adamala demonstrated that non-enzymatic RNA replication in primitive protocells is only possible in the presence of weak cation chelators like citric acid. This provides further evidence for the central role of citric acid in primordial metabolism. Russell has proposed that "the purpose of life is to hydrogenate carbon dioxide" (as part of a "metabolism-first", rather than a "genetics-first", scenario).The physicist Jeremy England has argued from general thermodynamic considerations that life was inevitable. An early version of this idea was Oparin's 1924 proposal for self-replicating vesicles. In the 1980s and 1990s came Wächtershäuser's iron–sulfur world theory and Christian de Duve's thioester models. More abstract and theoretical arguments for metabolism without genes include Freeman Dyson's mathematical model and Stuart Kauffman's collectively autocatalytic sets in the 1980s. Kauffman's work has been criticized for ignoring the role of energy in driving biochemical reactions in cells.

A multistep biochemical pathway like the Krebs cycle did not just self-organize on the surface of a mineral; it must have been preceded by simpler pathways. The Wood–Ljungdahl pathway is compatible with self-organization on a metal sulfide surface. Its key enzyme unit, carbon monoxide dehydrogenase/acetyl-CoA synthase, contains mixed nickel-iron-sulfur clusters in its reaction centers and catalyzes the formation of acetyl-CoA. However, prebiotic thiolated and thioester compounds are thermodynamically and kinetically unlikely to accumulate in the presumed prebiotic conditions of hydrothermal vents. One possibility is that cysteine and homocysteine may have reacted with nitriles from the Strecker reaction, forming catalytic thiol-rich polypeptides.

It has been suggested that the iron-sulfur world hypothesis and RNA world hypothesis are not mutually exclusive as modern cellular processes do involve both metabolites and genetic molecules.

Zinc world

Armen Mulkidjanian's zinc world (Zn-world) hypothesis extends Wächtershäuser's pyrite hypothesis. The Zn-world theory proposes that hydrothermal fluids rich in H₂S interacting with cold primordial ocean (or Darwin's "warm little pond") water precipitated metal sulfide particles. Oceanic hydrothermal systems have a zonal structure reflected in ancient volcanogenic massive sulfide ore deposits. They reach many kilometers in diameter and date back to the Archean. Most abundant are pyrite (FeS₂), chalcopyrite (CuFeS₂), and sphalerite (ZnS), with additions of galena (PbS) and alabandite (MnS). ZnS and MnS have a unique ability to store radiation energy, e.g. from ultraviolet light. When replicating molecules were originating, the primordial atmospheric pressure was high enough (>100 bar) to precipitate near the Earth's surface, and ultraviolet irradiation was 10 to 100 times more intense than now; hence the photosynthetic properties mediated by ZnS provided the right energy conditions for the synthesis of informational and metabolic molecules and the selection of photostable nucleobases.

The Zn-world theory has been filled out with evidence for the ionic constitution of the interior of the first protocells. In 1926, the Canadian biochemist Archibald Macallum noted the resemblance of body fluids such as blood and lymph to seawater; however, the inorganic composition of all cells differ from that of modern seawater, which led Mulkidjanian and colleagues to reconstruct the "hatcheries" of the first cells combining geochemical analysis with phylogenomic scrutiny of the inorganic ion requirements of modern cells. The authors conclude that ubiquitous, and by inference primordial, proteins and functional systems show affinity to and functional requirement for K⁺, Zn²⁺, Mn²⁺, and [PO
₄]³⁻
. Geochemical reconstruction shows that this ionic composition could not have existed in the ocean but is compatible with inland geothermal systems. In the oxygen-depleted, CO₂-dominated primordial atmosphere, the chemistry of water condensates near geothermal fields would resemble the internal milieu of modern cells. Therefore, precellular evolution may have taken place in shallow "Darwin ponds" lined with porous silicate minerals mixed with metal sulfides and enriched in K⁺, Zn²⁺, and phosphorus compounds.

Clay

The clay hypothesis was proposed by Graham Cairns-Smith in 1985. It postulates that complex organic molecules arose gradually on pre-existing, non-organic replication surfaces of silicate crystals in contact with an aqueous solution. The clay mineral montmorillonite has been shown to catalyze the polymerization of RNA in aqueous solution from nucleotide monomers, and the formation of membranes from lipids. In 1998, Hyman Hartman proposed that "the first organisms were self-replicating iron-rich clays which fixed carbon dioxide into oxalic acid and other dicarboxylic acids. This system of replicating clays and their metabolic phenotype then evolved into the sulfide rich region of the hot spring acquiring the ability to fix nitrogen. Finally phosphate was incorporated into the evolving system which allowed the synthesis of nucleotides and phospholipids."

Biochemistry

Different forms of life with variable origin processes may have appeared quasi-simultaneously in the early Earth. The other forms may be extinct, having left distinctive fossils through their different biochemistry. Metabolism-like reactions could have occurred naturally in early oceans, before the first organisms evolved. Some of these reactions can produce RNA, and others resemble two essential reaction cascades of metabolism: glycolysis and the pentose phosphate pathway, that provide essential precursors for nucleic acids, amino acids and lipids.

Fox proteinoids

In trying to uncover the intermediate stages of abiogenesis mentioned by Bernal, Sidney Fox in the 1950s and 1960s studied the spontaneous formation of peptide structures under plausibly early Earth conditions. In one of his experiments, he allowed amino acids to dry out as if puddled in a warm, dry spot in prebiotic conditions: In an experiment to set suitable conditions for life to form, Fox collected volcanic material from a cinder cone in Hawaii. He discovered that the temperature was over 100 °C just 4 inches (100 mm) beneath the surface of the cinder cone, and suggested that this might have been the environment in which life was created—molecules could have formed and then been washed through the loose volcanic ash into the sea. He placed lumps of lava over amino acids derived from methane, ammonia and water, sterilized all materials, and baked the lava over the amino acids for a few hours in a glass oven. A brown, sticky substance formed over the surface, and when the lava was drenched in sterilized water, a thick, brown liquid leached out. He found that, as they dried, the amino acids formed long, often cross-linked, thread-like, submicroscopic polypeptides.

Protein amyloid

An origin-of-life theory based on self-replicating beta-sheet structures has been put forward by Maury in 2009. The theory suggest that self-replicating and self-assembling catalytic amyloids were the first informational polymers in a primitive pre-RNA world. The main arguments for the amyloid hypothesis is based on the structural stability, autocatalytic and catalytic properties, and evolvability of beta-sheet based informational systems. Such systems are also error correcting and chiroselective.

First protein that condenses substrates during thermal cycling: thermosynthesis

Convection cells in fluid placed in a gravity field are selforganizing and enable thermal cycling of the suspended contents in the fluid such as protocells containing protoenzymes that work on thermal cycling.

The thermosynthesis hypothesis considers chemiosmosis more basal than fermentation: the ATP synthase enzyme, which sustains chemiosmosis, is the currently extant enzyme most closely related to the first metabolic process. The thermosynthesis hypothesis does not even invoke a pathway: ATP synthase's binding change mechanism resembles a physical adsorption process that yields free energy. The result would be convection which would bring a continual supply of reactants to the protoenzyme. The described first protein may be simple in the sense that it requires only a short sequence of conserved amino acid residues, a sequent sufficient for the appropriate catalytic cleft.

Pre-RNA world: The ribose issue and its bypass

A different type of nucleic acid, such as peptide nucleic acid, threose nucleic acid or glycol nucleic acid, could have been the first to emerge as a self-reproducing molecule, later replaced by RNA.Larralde et al., say that "the generally accepted prebiotic synthesis of ribose, the formose reaction, yields numerous sugars without any selectivity". They conclude that "the backbone of the first genetic material could not have contained ribose or other sugars because of their instability", meaning that the ester linkage of ribose and phosphoric acid in RNA is prone to hydrolysis.

Pyrimidine ribonucleosides and nucleotides have been synthesized by reactions which by-pass the free sugars, and are assembled stepwise using nitrogenous or oxygenous chemistries. Sutherland has demonstrated high-yielding routes to cytidine and uridine ribonucleotides from small 2 and 3 carbon fragments such as glycolaldehyde, glyceraldehyde or glyceraldehyde-3-phosphate, cyanamide and cyanoacetylene. A step in this sequence allows the isolation of enantiopure ribose aminooxazoline if the enantiomeric excess of glyceraldehyde is 60% or greater. This can be viewed as a prebiotic purification step. Ribose aminooxazoline can then react with cyanoacetylene to give alpha cytidine ribonucleotide. Photoanomerization with UV light allows for inversion about the 1' anomeric centre to give the correct beta stereochemistry. In 2009 they showed that the same simple building blocks allow access, via phosphate controlled nucleobase elaboration, to 2',3'-cyclic pyrimidine nucleotides directly, which can polymerize into RNA. Similar photo-sanitization can create pyrimidine-2',3'-cyclic phosphates.

Autocatalysis

Autocatalysts are substances that catalyze the production of themselves and therefore are "molecular replicators." The simplest self-replicating chemical systems are autocatalytic, and typically contain three components: a product molecule and two precursor molecules. The product molecule joins the precursor molecules, which in turn produce more product molecules from more precursor molecules. The product molecule catalyzes the reaction by providing a complementary template that binds to the precursors, thus bringing them together. Such systems have been demonstrated both in biological macromolecules and in small organic molecules.

It has been proposed that life initially arose as autocatalytic chemical networks. Julius Rebek and colleagues combined amino adenosine and pentafluorophenyl esters with the autocatalyst amino adenosine triacid ester (AATE). One product was a variant of AATE which catalyzed its own synthesis. This demonstrated that autocatalysts could compete within a population of entities with heredity, a rudimentary form of natural selection.

Synthesis based on hydrogen cyanide

A research project completed in 2015 by John Sutherland and others found that a network of reactions beginning with hydrogen cyanide and hydrogen sulfide, in streams of water irradiated by UV light, could produce the chemical components of proteins and lipids, as well as those of RNA, while not producing a wide range of other compounds. The researchers used the term "cyanosulfidic" to describe this network of reactions.

Simulated chemical pathways

In 2020, chemists described possible chemical pathways from nonliving prebiotic chemicals to complex biochemicals that could give rise to living organisms, based on a new computer program named AllChemy.

Viral origin

Evidence for a "virus first" hypothesis, which may support theories of the RNA world, was suggested in 2015. One of the difficulties for the study of the origins of viruses is their high rate of mutation; this is particularly the case in RNA retroviruses like HIV. A 2015 study compared protein fold structures across different branches of the tree of life, where researchers can reconstruct the evolutionary histories of the folds and of the organisms whose genomes code for those folds. They argue that protein folds are better markers of ancient events as their three-dimensional structures can be maintained even as the sequences that code for those begin to change. Thus, the viral protein repertoire retain traces of ancient evolutionary history that can be recovered using advanced bioinformatics approaches. Those researchers think that "the prolonged pressure of genome and particle size reduction eventually reduced virocells into modern viruses (identified by the complete loss of cellular makeup), meanwhile other coexisting cellular lineages diversified into modern cells." The data suggest that viruses originated from ancient cells that co-existed with the ancestors of modern cells. These ancient cells likely contained segmented RNA genomes.

A computational model (2015) has shown that virus capsids may have originated in the RNA world and served as a means of horizontal transfer between replicator communities. These communities could not survive if the number of gene parasites increased, with certain genes being responsible for the formation of these structures and those that favored the survival of self-replicating communities. The displacement of these ancestral genes between cellular organisms could favor the appearance of new viruses during evolution. Viruses retain a replication module inherited from the prebiotic stage since it is absent in cells. So this is evidence that viruses could originate from the RNA world and could also emerge several times in evolution through genetic escape in cells.

Encapsulation without a membrane

Polyester droplets

Tony Jia and Kuhan Chandru have proposed spontaneously-forming membraneless polyester droplets in early cellularization before the innovation of lipid vesicles. Protein function within and RNA function in the presence of certain polyester droplets was shown to be preserved within the droplets. The droplets have scaffolding ability, by allowing lipids to assemble around them; this may have prevented leakage of genetic materials.

Proteinoid microspheres

Fox observed in the 1960s that proteinoids could form cell-like structures named "proteinoid microspheres". The amino acids had combined to form proteinoids, which formed small globules. These were not cells; their clumps and chains were reminiscent of cyanobacteria, but they contained no functional nucleic acids or other encoded information. Colin Pittendrigh stated in 1967 that "laboratories will be creating a living cell within ten years", a remark that reflected the typical contemporary naivety about the complexity of cell structures.

Jeewanu protocell

A further protocell model is the Jeewanu. First synthesized in 1963 from simple minerals and basic organics while exposed to sunlight, it is reported to have some metabolic capabilities, the presence of a semipermeable membrane, amino acids, phospholipids, carbohydrates and RNA-like molecules.However, the nature and properties of the Jeewanu remains to be clarified. Electrostatic interactions induced by short, positively charged, hydrophobic peptides containing 7 amino acids in length or fewer can attach RNA to a vesicle membrane, the basic cell membrane.

RNA-DNA world

In 2020, coevolution of a RNA-DNA mixture based on diamidophosphate was proposed.The mixture of RNA-DNA sequences, called chimeras, have weak affinity and form weaker duplex structures. This is advantageous in an abiotic scenario and these chimeras have been shown to replicate RNA and DNA – overcoming the "template-product" inhibition problem, where a pure RNA or pure DNA strand is unable to replicate non-enzymatically because it binds too strongly to its partners. This could lead to an abiotic cross-catalytic amplification of RNA and DNA. A continuous chemical reaction network in water and under high-energy radiation can generate precursors for early RNA.

In 2022, evolution experiments of self-replicating RNA showed how RNA may have evolved to diverse complex molecules in RNA world conditions. The RNA evolved to a "replicator network comprising five types of RNAs with diverse interactions" such as cooperation for replication of other members (multiple coexisting host and parasite lineages).

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