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
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.
Blood–brain barrier
methods of transport. Given the large and charged size of cytokines,
active transport is the only direct way for the same cytokine
circulating in the blood to pass through an intact blood-brain barrier.
Other methods, such as activation of the endothelial cells, cytokine
signaling, recruitment of granulocyte cells, and activation of afferent
neurons work indirectly and cause the creation or 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.
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.
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 physicistJeremy 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.
The active site of the acetyl-CoA synthase enzyme, part of the acetyl-CoA pathway, contains nickel-iron-sulfur clusters.
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 mineralmontmorillonite 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.
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).
The introduction of cisplatin as a standard treatment for
testicular cancer improved remission rates from 5-10% before 1974 to
75-85% by 1984.
Side effects
Cisplatin has a number of side effects that can limit its use:
Nephrotoxicity
(kidney damage) is the primary dose-limiting side effect and is of
major clinical concern. Cisplatin selectively accumulates into the proximal tubule via basolateral-to-apical transport, where it disrupts mitochondrial energetics and endoplasmic reticulum Ca2+ homeostasis and stimulates reactive oxygen species and pro-inflammatory cytokines. Multiple mitigation strategies are being explored clinically and pre-clinically, including hydration regimens, amifostine, transporter inhibitors, antioxidants, anti-inflammatories, and epoxyeicosatrienoic acids and their analogues.
Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction studies
before and after treatment. Common neurological side effects of
cisplatin include visual perception and hearing disorder, which can
occur soon after treatment begins.
While triggering apoptosis through interfering with DNA replication
remains the primary mechanism of cisplatin, this has not been found to
contribute to neurological side effects. Recent studies have shown that
cisplatin noncompetitively inhibits an archetypal, membrane-bound
mechanosensitive sodium-hydrogen ion transporter known as NHE-1.
It is primarily found on cells of the peripheral nervous system, which
are aggregated in large numbers near the ocular and aural
stimuli-receiving centers. This noncompetitive interaction has been
linked to hydroelectrolytic imbalances and cytoskeleton alterations,
both of which have been confirmed in vitro and in vivo. However, NHE-1
inhibition has been found to be both dose-dependent (half-inhibition =
30 μg/mL) and reversible. Cisplatin can increase levels of sphingosine-1-phosphate in the central nervous system, contributing to the development of post-chemotherapy cognitive impairment.
Ototoxicity and hearing loss associated with cisplatin can be severe and is considered to be a dose-limiting side effect. Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs (such as the aminoglycoside
antibiotic class) may also cause ototoxicity, and the administration of
this class of antibiotics in patients receiving cisplatin is generally
avoided. The ototoxicity of both the aminoglycosides and cisplatin may
be related to their ability to bind to melanin in the stria vascularis of the inner ear or the generation of reactive oxygen species. In September 2022, the U.S. Food and Drug Administration (FDA) approved sodium thiosulfate under the brand name Pedmark to lessen the risk of ototoxicity and hearing loss in people receiving cisplatin. There is ongoing investigation of acetylcysteine injections as a preventative measure.
Electrolyte disturbance:
Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia.
The hypocalcaemia seems to occur in those with low serum magnesium
secondary to cisplatin, so it is not primarily due to the cisplatin.
Hemolytic anemia
can be developed after several courses of cisplatin. It is suggested
that an antibody reacting with a cisplatin-red-cell membrane is
responsible for hemolysis.
Pharmacology
Cisplatin
interferes with DNA replication, which kills the fastest proliferating
cells, which in theory are cancerous. Following administration, one
chloride ion is slowly displaced by water to give the aquo complexcis-[PtCl(NH3)2(H2O)]+, in a process termed aquation.
Dissociation of the chloride is favored inside the cell because the
intracellular chloride concentration is only 3–20% of the approximately
100 mM chloride concentration in the extracellular fluid.
The water molecule in cis-[PtCl(NH3)2(H2O)]+ is itself easily displaced by the N-heterocyclic bases on DNA. Guanine preferentially binds. A model compound has been prepared and crystals were examined by X-ray crystallography
Subsequent to formation of [PtCl(guanine-DNA)(NH3)2]+, crosslinking can occur via displacement of the other chloride, typically by another guanine. Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis. The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis
when repair proves impossible. In 2008, researchers were able to show
that the apoptosis induced by cisplatin on human colon cancer cells
depends on the mitochondrial serine-protease Omi/Htra2.
Since this was only demonstrated for colon carcinoma cells, it remains
an open question whether the Omi/Htra2 protein participates in the
cisplatin-induced apoptosis in carcinomas from other tissues.
Most notable among the changes in DNA are the 1,2-intrastrand cross-links with purine bases. These include 1,2-intrastrand d(GpG) adducts, which form nearly 90% of the adducts, and the less common 1,2-intrastrand d(ApG)
adducts. Coordination chemists have obtained crystals of the products
of reacting cisplain with small models of DNA. Here is a POVray plot of the platinum binding to a small model of DNA.
A
POVray plot of the atomic coordinates for the cis Pt(NH3)2 and short
fragment of DNA which was reported by Stephen J. Lippard in Science 1985
1,3-intrastrand d(GpXpG) adducts occur but are readily excised by the nucleotide excision repair (NER).
Other adducts include inter-strand crosslinks and nonfunctional adducts
that have been postulated to contribute to cisplatin's activity.
Interaction with cellular proteins, particularly HMG
domain proteins, has also been advanced as a mechanism of interfering
with mitosis, although this is probably not its primary method of
action.
Cisplatin resistance
Cisplatin
combination chemotherapy is the cornerstone of treatment of many
cancers. Initial platinum responsiveness is high, but the majority of
cancer patients will eventually relapse with cisplatin-resistant
disease. Many mechanisms of cisplatin resistance have been proposed,
including changes in cellular uptake and efflux of the drug, increased
detoxification of the drug, inhibition of apoptosis , increased DNA repair or changes in metabolism. Oxaliplatin
is active in highly cisplatin-resistant cancer cells in the laboratory;
however, there is little evidence for its activity in the clinical
treatment of patients with cisplatin-resistant cancer. The drug paclitaxel may be useful in the treatment of cisplatin-resistant cancer; the mechanism for this activity is as yet unknown.
Transplatin
Transplatin, the trans-stereoisomer of cisplatin, has formula trans-[PtCl2(NH3)2]
and does not exhibit a comparably useful pharmacological effect. Two
mechanisms have been suggested to explain the reduced anticancer effect
of transplatin. Firstly, the trans arrangement of the chloro
ligands is thought to confer transplatin with greater chemical
reactivity, causing transplatin to become deactivated before it reaches
the DNA, where cisplatin exerts its pharmacological action. Secondly,
the stereo-conformation of transplatin is such that it is unable to form
the characteristic 1,2-intrastrand d(GpG) adducts formed by cisplatin
in abundance.
Molecular structure
Cisplatin is the square planarcoordination complex cis-[Pt(NH3)2Cl2]. The prefix cis indicates the cis isomer in which two similar ligands are in adjacent positions. The systematic chemical name of this molecule is cis–diamminedichloroplatinum, where ammine with two m's indicates an ammonia (NH3) ligand, as opposed to an organic amine with one m.
Solution structure of cisplatin (highlighted) interstrand GG adducts with double-stranded DNA. (PDB: 1DDP)
2.60Å resolution crystal structure of
cisplatin (highlighted) intrastrand GG adducts with double-stranded DNA.
Note: the hydrogens on amine ligands are not shown. (PDB: 1AIO)
History
The compound cis-[Pt(NH3)2Cl2] was first described by Italian chemist Michele Peyrone in 1845, and known for a long time as Peyrone's salt. The structure was deduced by Alfred Werner in 1893. In 1965, Barnett Rosenberg, Van Camp et al. of Michigan State University discovered that electrolysis of platinum electrodes generated a soluble platinum complex which inhibited binary fission in Escherichia coli (E. coli)
bacteria. Although bacterial cell growth continued, cell division was
arrested, the bacteria growing as filaments up to 300 times their normal
length. The octahedral Pt(IV) complex cis-[PtCl4(NH3)2], but not the trans isomer, was found to be effective at forcing filamentous growth of E. coli cells. The square planar Pt(II) complex, cis-[PtCl2(NH3)2] turned out to be even more effective at forcing filamentous growth.[ This finding led to the observation that cis-[PtCl2(NH3)2] was indeed highly effective at regressing the mass of sarcomas in rats.
Confirmation of this discovery, and extension of testing to other
tumour cell lines launched the medicinal applications of cisplatin.
Cisplatin was approved for use in testicular and ovarian cancers by the
U.S. Food and Drug Administration on 19 December 1978. and in the UK (and in several other European countries) in 1979.
Cisplatin was the first to be developed.
In 1983 pediatric oncologist Roger Packer began incorporating cisplatin
into adjuvant chemotherapy for the treatment of childhood medulloblastoma.
The new protocol that he developed led to a marked increase in
disease-free survival rates for patients with medulloblastoma, up to
around 85%.
The Packer Protocol has since become a standard treatment for
medulloblastoma. Likewise, cisplatin has been found to be particularly
effective against testicular cancer, where its use improved the cure rate from 10% to 85%.
Recently, some researchers have investigated at the preclinical level new forms of cisplatin prodrugs in combination with nanomaterials in order to localize the release of the drug in the target.
Synthesis
Syntheses of cisplatin start from potassium tetrachloroplatinate. Several procedures are available. One obstacle is the facile formation of Magnus's green salt (MGS), which has the same empirical formula as cisplatin. The traditional way to avoid MGS involves the conversion of K2PtCl4 to K2PtI4, as originally described by Dhara. Reaction with ammonia forms PtI2(NH3)2 which is isolated as a yellow compound. When silver nitrate in water is added insoluble silver iodide precipitates and [Pt(OH2)2(NH3)2](NO3)2 remains in solution. Addition of potassium chloride will form the final product which precipitates In the triiodo intermediate the addition of the second ammonia ligand is governed by the trans effect.
A one-pot synthesis of cisplatin from K2PtCl4 has been developed. It relies on the slow release of ammonia from ammonium acetate.
Research
Cisplatin has been studied with Auger therapy to increase the therapeutic effects of cisplatin, without increasing normal tissue toxicities.
However, due to significant side effects, the search for structurally
novel Pt(II) and Pd(II) compounds exhibiting antineoplastic activity is
extremely important and aims to develop more effective and less toxic
drugs. Metal complexes comprising cisplatin-like molecules ([PtCl(NH3)2] or [Pt(NH3)Cl2])
linked by variable length alkandiamine chains have attracted great
interest in the last few years as next-generation alternatives drugs in
cancer chemotherapy.
![Iron-Sulphur minerals like Greigite catalyse the reduction of carbon dioxide in hydrothermal vents to make Krebs cycle intermediates.[2]](https://en.wikipedia.org/wiki/File:Abiogenesis_Scenario_1.svg)
![Protocells in contact with a thin rock barrier in a hydrothermal vent get a free supply of energy from the pH gradient.[3]](https://en.wikipedia.org/wiki/File:Abiogenesis_Scenario_2.svg)
![Protocells in a hydrothermal vent can grow by adding fatty acids to their membrane, other organics to their cytoplasm.[4]](https://en.wikipedia.org/wiki/File:Abiogenesis_Scenario_3.svg)
![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.[5]](https://en.wikipedia.org/wiki/File:Abiogenesis_Scenario_4.svg)
![A protocell away from a hydrothermal vent must create its own proton-motive force, such as by splitting hydrogen sulphide.[6]](https://en.wikipedia.org/wiki/File:Abiogenesis_Scenario_5.svg)
![Ferredoxin catalyses the splitting of hydrogen sulphide, its earliest repeating amino acid sequence perhaps coded for by an incomplete genetic code.[7]](https://en.wikipedia.org/wiki/File:Abiogenesis_Scenario_6.svg)
![Anoxygenic photosynthesis, using hydrogen sulphide, ended the need for scarce hydrogen.[7]](https://en.wikipedia.org/wiki/File:Abiogenesis_Scenario_7.svg)
![Early heterotrophs used Krebs cycle respiration; then oxygenic photosynthesis gave full independence of volcanic energy.[7]](https://en.wikipedia.org/wiki/File:Abiogenesis_Scenario_8.svg)
