Adenosine triphosphate

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

Adenosine triphosphate

Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy of approximate 30.5kJ/mol to drive and support many processes in living cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known forms of life, it is often referred to as the "molecular unit of currency" for intracellular energy transfer.

When consumed in a metabolic process, ATP converts either to adenosine diphosphate (ADP) or to adenosine monophosphate (AMP). Other processes regenerate ATP. It is also a precursor to DNA and RNA, and is used as a coenzyme. An average adult human processes around 50 kilograms (about 100 moles) daily.

From the perspective of biochemistry, ATP is classified as a nucleoside triphosphate, which indicates that it consists of three components: a nitrogenous base (adenine), the sugar ribose, and the triphosphate.

Structure

ATP consists of three parts: a sugar, an amine base, and a phosphate group. More specifically, ATP consists of an adenine attached by the #9-nitrogen atom to the 1′ carbon atom of a sugar (ribose), which in turn is attached at the 5' carbon atom of the sugar to a triphosphate group. In its many reactions related to metabolism, the adenine and sugar groups remain unchanged, but the triphosphate is converted to di- and monophosphate, giving respectively the derivatives ADP and AMP. The three phosphoryl groups are labeled as alpha (α), beta (β), and, for the terminal phosphate, gamma (γ).

In neutral solution, ionized ATP exists mostly as ATP⁴⁻, with a small proportion of ATP³⁻.

Metal cation binding

Polyanionic and featuring a potentially chelating polyphosphate group, ATP binds metal cations with high affinity. The binding constant for Mg²⁺ is (9554). The binding of a divalent cation, almost always magnesium, strongly affects the interaction of ATP with various proteins. Due to the strength of the ATP-Mg²⁺ interaction, ATP exists in the cell mostly as a complex with Mg²⁺ bonded to the phosphate oxygen centers.

A second magnesium ion is critical for ATP binding in the kinase domain. The presence of Mg²⁺ regulates kinase activity. It is interesting from an RNA world perspective that ATP can carry a Mg ion which catalyzes RNA polymerization.

Chemical properties

Salts of ATP can be isolated as colorless solids.

The cycles of synthesis and degradation of ATP; 2 and 1 represent input and output of energy, respectively.

ATP is stable in aqueous solutions between pH 6.8 and 7.4 (in the absence of catalysts). At more extreme pH levels, it rapidly hydrolyses to ADP and phosphate. Living cells maintain the ratio of ATP to ADP at a point ten orders of magnitude from equilibrium, with ATP concentrations fivefold higher than the concentration of ADP. In the context of biochemical reactions, the P-O-P bonds are frequently referred to as high-energy bonds.

Reactive aspects

The hydrolysis of ATP into ADP and inorganic phosphate:

ATP⁴⁻ + H₂O ⇌ ADP³⁻ + HPO2−3 + H⁺

releases 20.5 kilojoules per mole (4.9 kcal/mol) of enthalpy. This may differ under physiological conditions if the reactant and products are not exactly in these ionization states. The values of the free energy released by cleaving either a phosphate (P_i) or a pyrophosphate (PP_i) unit from ATP at standard state concentrations of 1 mol/L at pH 7 are:

ATP + H₂O → ADP + P_i   ΔG°' = −30.5 kJ/mol (−7.3 kcal/mol)

ATP + H₂O → AMP + PP_i  ΔG°' = −45.6 kJ/mol (−10.9 kcal/mol)

These abbreviated equations at a pH near 7 can be written more explicitly (R = adenosyl):

[RO−P(O)₂−O−P(O)₂−O−PO₃]⁴⁻ + H₂O → [RO−P(O)₂−O−PO₃]³⁻ + [HPO₄]²⁻ + H⁺

[RO−P(O)₂−O−P(O)₂−O−PO₃]⁴⁻ + H₂O → [RO−PO₃]²⁻ + [HO₃P−O−PO₃]³⁻ + H⁺

At cytoplasmic conditions, where the ADP/ATP ratio is 10 orders of magnitude from equilibrium, the ΔG is around −57 kJ/mol.

Along with pH, the free energy change of ATP hydrolysis is also associated with Mg²⁺ concentration, from ΔG°' = −35.7 kJ/mol at a Mg²⁺ concentration of zero, to ΔG°' = −31 kJ/mol at [Mg²⁺] = 5 mM. Higher concentrations of Mg²⁺ decrease free energy released in the reaction due to binding of Mg²⁺ ions to negatively charged oxygen atoms of ATP at pH 7.

This image shows a 360-degree rotation of a single, gas-phase magnesium-ATP chelate with a charge of −2. The anion was optimized at the UB3LYP/6-311++G(d,p) theoretical level and the atomic connectivity modified by the human optimizer to reflect the probable electronic structure.

Production from AMP and ADP

Production, aerobic conditions

A typical intracellular concentration of ATP is 1–10 μmol per gram of muscle tissue in a variety of eukaryotes. The dephosphorylation of ATP and rephosphorylation of ADP and AMP occur repeatedly in the course of aerobic metabolism.

ATP can be produced by a number of distinct cellular processes; the three main pathways in eukaryotes are (1) glycolysis, (2) the citric acid cycle/oxidative phosphorylation, and (3) beta-oxidation. The overall process of oxidizing glucose to carbon dioxide, the combination of pathways 1 and 2, known as cellular respiration, produces about 30 equivalents of ATP from each molecule of glucose.

ATP production by a non-photosynthetic aerobic eukaryote occurs mainly in the mitochondria, which comprise nearly 25% of the volume of a typical cell.

Glycolysis

Main article: Glycolysis

In glycolysis, glucose and glycerol are metabolized to pyruvate. Glycolysis generates two equivalents of ATP through substrate phosphorylation catalyzed by two enzymes, phosphoglycerate kinase (PGK) and pyruvate kinase. Two equivalents of nicotinamide adenine dinucleotide (NADH) are also produced, which can be oxidized via the electron transport chain and result in the generation of additional ATP by ATP synthase. The pyruvate generated as an end-product of glycolysis is a substrate for the Krebs Cycle.

Glycolysis is viewed as consisting of two phases with five steps each. In phase 1, "the preparatory phase", glucose is converted to 2 d-glyceraldehyde-3-phosphate (g3p). One ATP is invested in Step 1, and another ATP is invested in Step 3. Steps 1 and 3 of glycolysis are referred to as "Priming Steps". In Phase 2, two equivalents of g3p are converted to two pyruvates. In Step 7, two ATP are produced. Also, in Step 10, two further equivalents of ATP are produced. In Steps 7 and 10, ATP is generated from ADP. A net of two ATPs is formed in the glycolysis cycle. The glycolysis pathway is later associated with the Citric Acid Cycle which produces additional equivalents of ATP.

Regulation

In glycolysis, hexokinase is directly inhibited by its product, glucose-6-phosphate, and pyruvate kinase is inhibited by ATP itself. The main control point for the glycolytic pathway is phosphofructokinase (PFK), which is allosterically inhibited by high concentrations of ATP and activated by high concentrations of AMP. The inhibition of PFK by ATP is unusual since ATP is also a substrate in the reaction catalyzed by PFK; the active form of the enzyme is a tetramer that exists in two conformations, only one of which binds the second substrate fructose-6-phosphate (F6P). The protein has two binding sites for ATP – the active site is accessible in either protein conformation, but ATP binding to the inhibitor site stabilizes the conformation that binds F6P poorly. A number of other small molecules can compensate for the ATP-induced shift in equilibrium conformation and reactivate PFK, including cyclic AMP, ammonium ions, inorganic phosphate, and fructose-1,6- and -2,6-biphosphate.

Citric acid cycle

Main articles: Citric acid cycle and Oxidative phosphorylation

In the mitochondrion, pyruvate is oxidized by the pyruvate dehydrogenase complex to the acetyl group, which is fully oxidized to carbon dioxide by the citric acid cycle (also known as the Krebs cycle). Every "turn" of the citric acid cycle produces two molecules of carbon dioxide, one equivalent of ATP guanosine triphosphate (GTP) through substrate-level phosphorylation catalyzed by succinyl-CoA synthetase, as succinyl-CoA is converted to succinate, three equivalents of NADH, and one equivalent of FADH₂. NADH and FADH₂ are recycled (to NAD⁺ and FAD, respectively) by oxidative phosphorylation, generating additional ATP. The oxidation of NADH results in the synthesis of 2–3 equivalents of ATP, and the oxidation of one FADH₂ yields between 1–2 equivalents of ATP. The majority of cellular ATP is generated by this process. Although the citric acid cycle itself does not involve molecular oxygen, it is an obligately aerobic process because O₂ is used to recycle the NADH and FADH₂. In the absence of oxygen, the citric acid cycle ceases.

The generation of ATP by the mitochondrion from cytosolic NADH relies on the malate-aspartate shuttle (and to a lesser extent, the glycerol-phosphate shuttle) because the inner mitochondrial membrane is impermeable to NADH and NAD⁺. Instead of transferring the generated NADH, a malate dehydrogenase enzyme converts oxaloacetate to malate, which is translocated to the mitochondrial matrix. Another malate dehydrogenase-catalyzed reaction occurs in the opposite direction, producing oxaloacetate and NADH from the newly transported malate and the mitochondrion's interior store of NAD⁺. A transaminase converts the oxaloacetate to aspartate for transport back across the membrane and into the intermembrane space.

In oxidative phosphorylation, the passage of electrons from NADH and FADH₂ through the electron transport chain releases the energy to pump protons out of the mitochondrial matrix and into the intermembrane space. This pumping generates a proton motive force that is the net effect of a pH gradient and an electric potential gradient across the inner mitochondrial membrane. Flow of protons down this potential gradient – that is, from the intermembrane space to the matrix – yields ATP by ATP synthase. Three ATP are produced per turn.

Although oxygen consumption appears fundamental for the maintenance of the proton motive force, in the event of oxygen shortage (hypoxia), intracellular acidosis (mediated by enhanced glycolytic rates and ATP hydrolysis), contributes to mitochondrial membrane potential and directly drives ATP synthesis.

Most of the ATP synthesized in the mitochondria will be used for cellular processes in the cytosol; thus it must be exported from its site of synthesis in the mitochondrial matrix. ATP outward movement is favored by the membrane's electrochemical potential because the cytosol has a relatively positive charge compared to the relatively negative matrix. For every ATP transported out, it costs 1 H⁺. Producing one ATP costs about 3 H⁺. Therefore, making and exporting one ATP requires 4H^+. The inner membrane contains an antiporter, the ADP/ATP translocase, which is an integral membrane protein used to exchange newly synthesized ATP in the matrix for ADP in the intermembrane space.

Regulation

The citric acid cycle is regulated mainly by the availability of key substrates, particularly the ratio of NAD⁺ to NADH and the concentrations of calcium, inorganic phosphate, ATP, ADP, and AMP. Citrate – the ion that gives its name to the cycle – is a feedback inhibitor of citrate synthase and also inhibits PFK, providing a direct link between the regulation of the citric acid cycle and glycolysis.

Beta oxidation

Main article: Beta-oxidation

In the presence of air and various cofactors and enzymes, fatty acids are converted to acetyl-CoA. The pathway is called beta-oxidation. Each cycle of beta-oxidation shortens the fatty acid chain by two carbon atoms and produces one equivalent each of acetyl-CoA, NADH, and FADH₂. The acetyl-CoA is metabolized by the citric acid cycle to generate ATP, while the NADH and FADH₂ are used by oxidative phosphorylation to generate ATP. Dozens of ATP equivalents are generated by the beta-oxidation of a single long acyl chain.

Regulation

In oxidative phosphorylation, the key control point is the reaction catalyzed by cytochrome c oxidase, which is regulated by the availability of its substrate – the reduced form of cytochrome c. The amount of reduced cytochrome c available is directly related to the amounts of other substrates:

${\displaystyle \frac{1}{2}\text{NADH}+\text{cyt}{\text{c}}_{\text{ox}}^{}+\text{ADP}+{\text{P}}_{\text{i}}^{}\rightleftharpoons \frac{1}{2}{\text{NAD}}^{+}+\text{cyt}{\text{c}}_{\text{red}}^{}+\text{ATP}}$

which directly implies this equation:

${\displaystyle \frac{[\mathrm{c}\mathrm{y}\mathrm{t}{\mathrm{c}}_{\mathrm{r}\mathrm{e}\mathrm{d}}]}{[\mathrm{c}\mathrm{y}\mathrm{t}{\mathrm{c}}_{\mathrm{o}\mathrm{x}}]}={\left(\frac{[\mathrm{N}\mathrm{A}\mathrm{D}\mathrm{H}]}{[\mathrm{N}\mathrm{A}\mathrm{D}{]}^{+}}\right)}^{\frac{1}{2}}\left(\frac{[\mathrm{A}\mathrm{D}\mathrm{P}][{\mathrm{P}}_{\mathrm{i}}]}{[\mathrm{A}\mathrm{T}\mathrm{P}]}\right)K_{\mathrm{e}\mathrm{q}}}$

Thus, a high ratio of [NADH] to [NAD⁺] or a high ratio of [ADP] [P_i] to [ATP] imply a high amount of reduced cytochrome c and a high level of cytochrome c oxidase activity. An additional level of regulation is introduced by the transport rates of ATP and NADH between the mitochondrial matrix and the cytoplasm.

Ketosis

Main article: Ketone bodies

Ketone bodies can be used as fuels, yielding 22 ATP and 2 GTP molecules per acetoacetate molecule when oxidized in the mitochondria. Ketone bodies are transported from the liver to other tissues, where acetoacetate and beta-hydroxybutyrate can be reconverted to acetyl-CoA to produce reducing equivalents (NADH and FADH₂), via the citric acid cycle. Ketone bodies cannot be used as fuel by the liver, because the liver lacks the enzyme β-ketoacyl-CoA transferase, also called thiolase. Acetoacetate in low concentrations is taken up by the liver and undergoes detoxification through the methylglyoxal pathway which ends with lactate. Acetoacetate in high concentrations is absorbed by cells other than those in the liver and enters a different pathway via 1,2-propanediol. Though the pathway follows a different series of steps requiring ATP, 1,2-propanediol can be turned into pyruvate.

Production, anaerobic conditions

Fermentation is the metabolism of organic compounds in the absence of air. It involves substrate-level phosphorylation in the absence of a respiratory electron transport chain.

The equation for the reaction of glucose to form lactic acid is:

C₆H₁₂O₆ + 2 ADP + 2 P_i → 2 CH₃CH(OH)COOH + 2 ATP + 2 H₂O

Anaerobic respiration is respiration in the absence of O₂. Prokaryotes can utilize a variety of electron acceptors. These include nitrate, sulfate, and carbon dioxide. In anaerobic organisms and prokaryotes, different pathways result in ATP. ATP is produced in the chloroplasts of green plants in a process similar to oxidative phosphorylation, called photophosphorylation.

ATP replenishment by nucleoside diphosphate kinases

ATP can also be synthesized through several so-called "replenishment" reactions catalyzed by the enzyme families of nucleoside diphosphate kinases (NDKs), which use other nucleoside triphosphates as a high-energy phosphate donor, and the ATP:guanido-phosphotransferase family.

ATP production during photosynthesis

In plants, ATP is synthesized in the thylakoid membrane of the chloroplast. The process is called photophosphorylation. The "machinery" is similar to that in mitochondria except that light energy is used to pump protons across a membrane to produce a proton-motive force. ATP synthase then ensues exactly as in oxidative phosphorylation. Some of the ATP produced in the chloroplasts is consumed in the Calvin cycle, which produces triose sugars.

ATP recycling

The total quantity of ATP in the human body is about 0.1 mol/L. The majority of ATP is recycled from ADP by the aforementioned processes. Thus, at any given time, the total amount of ATP + ADP remains fairly constant.

The energy used by human cells in an adult requires the hydrolysis of 100 to 150 mol/L of ATP daily, which means a human will typically use their body weight worth of ATP over the course of the day. Each equivalent of ATP is recycled 1000–1500 times during a single day (150 / 0.1 = 1500), at approximately 9×10²⁰ molecules/s.

An example of the Rossmann fold, a structural domain of a decarboxylase enzyme from the bacterium Staphylococcus epidermidis (PDB: 1G5Q​) with a bound flavin mononucleotide cofactor

Biochemical functions

Cellular energy production

The conversion of ATP to ADP is the principal mechanism for energy supply in biological processes. Energy is produced in cells when the terminal phosphate group in an ATP molecule is removed from the chain to produce adenosine diphosphate (ADP) when water hydrolyzes ATP:

ATP + H₂O → ADP + HPO₄^2- + H⁺ + energy

However, removing a phosphate group from ADP to produce adenosine monophosphate (AMP) also produces extra energy.

Intracellular signaling

ATP is involved in signal transduction by serving as substrate for kinases, enzymes that transfer phosphate groups. Kinases are the most common ATP-binding proteins. They share a small number of common folds. Phosphorylation of a protein by a kinase can activate a cascade such as the mitogen-activated protein kinase cascade.

ATP is also a substrate of adenylate cyclase, most commonly in G protein-coupled receptor signal transduction pathways and is transformed to second messenger, cyclic AMP, which is involved in triggering calcium signals by the release of calcium from intracellular stores. This form of signal transduction is particularly important in brain function, although it is involved in the regulation of a multitude of other cellular processes.

DNA and RNA synthesis

ATP is one of four monomers required in the synthesis of RNA. The process is promoted by RNA polymerases. A similar process occurs in the formation of DNA, except that ATP is first converted to the deoxyribonucleotide dATP. Like many condensation reactions in nature, DNA replication and DNA transcription also consume ATP.

Amino acid activation in protein synthesis

Main article: Amino acid activation

Aminoacyl-tRNA synthetase enzymes consume ATP in the attachment tRNA to amino acids, forming aminoacyl-tRNA complexes. Aminoacyl transferase binds AMP-amino acid to tRNA. The coupling reaction proceeds in two steps:

1. aa + ATP ⟶ aa-AMP + PP_i
2. aa-AMP + tRNA ⟶ aa-tRNA + AMP

The amino acid is coupled to the penultimate nucleotide at the 3′-end of the tRNA (the A in the sequence CCA) via an ester bond (roll over in illustration).

ATP binding cassette transporter

Transporting chemicals out of a cell against a gradient is often associated with ATP hydrolysis. Transport is mediated by ATP binding cassette transporters. The human genome encodes 48 ABC transporters, that are used for exporting drugs, lipids, and other compounds.

Extracellular signalling and neurotransmission

Cells secrete ATP to communicate with other cells in a process called purinergic signalling. ATP serves as a neurotransmitter in many parts of the nervous system, modulates ciliary beating, affects vascular oxygen supply etc. ATP is either secreted directly across the cell membrane through channel proteins or is pumped into vesicles which then fuse with the membrane. Cells detect ATP using the purinergic receptor proteins P2X and P2Y. ATP has been shown to be a critically important signalling molecule for microglia - neuron interactions in the adult brain, as well as during brain development. Furthermore, tissue-injury induced ATP-signalling is a major factor in rapid microglial phenotype changes.

Muscle contraction

ATP fuels muscle contractions. Muscle contractions are regulated by signaling pathways, although different muscle types being regulated by specific pathways and stimuli based on their particular function. However, in all muscle types, contraction is performed by the proteins actin and myosin.

ATP is initially bound to myosin. When ATPase hydrolyzes the bound ATP into ADP and inorganic phosphate, myosin is positioned in a way that it can bind to actin. Myosin bound by ADP and P_i forms cross-bridges with actin and the subsequent release of ADP and P_i releases energy as the power stroke. The power stroke causes actin filament to slide past the myosin filament, shortening the muscle and causing a contraction. Another ATP molecule can then bind to myosin, releasing it from actin and allowing this process to repeat.

Protein solubility

ATP has recently been proposed to act as a biological hydrotrope and has been shown to affect proteome-wide solubility.

Abiogenic origins

Acetyl phosphate (AcP), a precursor to ATP, can readily be synthesized at modest yields from thioacetate in pH 7 and 20 °C and pH 8 and 50 °C, although acetyl phosphate is less stable in warmer temperatures and alkaline conditions than in cooler and acidic to neutral conditions. It is unable to promote polymerization of ribonucleotides and amino acids and was only capable of phosphorylation of organic compounds. It was shown that it can promote aggregation and stabilization of AMP in the presence of Na⁺, aggregation of nucleotides could promote polymerization above 75 °C in the absence of Na⁺. It is possible that polymerization promoted by AcP could occur at mineral surfaces. It was shown that ADP can only be phosphorylated to ATP by AcP and other nucleoside triphosphates were not phosphorylated by AcP. This might explain why all lifeforms use ATP to drive biochemical reactions.

ATP analogues

Biochemistry laboratories often use in vitro studies to explore ATP-dependent molecular processes. ATP analogs are also used in X-ray crystallography to determine a protein structure in complex with ATP, often together with other substrates.

Enzyme inhibitors of ATP-dependent enzymes such as kinases are needed to examine the binding sites and transition states involved in ATP-dependent reactions.

Most useful ATP analogs cannot be hydrolyzed as ATP would be; instead, they trap the enzyme in a structure closely related to the ATP-bound state. Adenosine 5′-(γ-thiotriphosphate) is an extremely common ATP analog in which one of the gamma-phosphate oxygens is replaced by a sulfur atom; this anion is hydrolyzed at a dramatically slower rate than ATP itself and functions as an inhibitor of ATP-dependent processes. In crystallographic studies, hydrolysis transition states are modeled by the bound vanadate ion.

Caution is warranted in interpreting the results of experiments using ATP analogs, since some enzymes can hydrolyze them at appreciable rates at high concentration.

Medical use

ATP is used intravenously for some heart-related conditions.

History

ATP was discovered in 1929 from muscle tissue by Karl Lohmann [de] and Jendrassik and, independently, by Cyrus Fiske and Yellapragada Subba Rao of Harvard Medical School, both teams competing against each other to find an assay for phosphorus.

It was proposed to be the intermediary between energy-yielding and energy-requiring reactions in cells by Fritz Albert Lipmann in 1941. He played a major role in establishing that ATP is the energy currency of a cell.

It was first synthesized in the laboratory by Alexander Todd in 1948, and he was awarded the Nobel Prize in Chemistry in 1957 partly for this work.

The 1978 Nobel Prize in Chemistry was awarded to Peter Dennis Mitchell for the discovery of the chemiosmotic mechanism of ATP synthesis.

The 1997 Nobel Prize in Chemistry was divided, one half jointly to Paul D. Boyer and John E. Walker "for their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)" and the other half to Jens C. Skou "for the first discovery of an ion-transporting enzyme, Na⁺, K⁺ -ATPase."

Abrupt climate change

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

Clathrate hydrates have been identified as a possible agent for abrupt changes.

An abrupt climate change occurs when the climate system is forced to transition at a rate that is determined by the climate system energy-balance. The transition rate is more rapid than the rate of change of the external forcing, though it may include sudden forcing events such as meteorite impacts. Abrupt climate change therefore is a variation beyond the variability of a climate. Past events include the end of the Carboniferous Rainforest Collapse, Younger Dryas, Dansgaard–Oeschger events, Heinrich events and possibly also the Paleocene–Eocene Thermal Maximum. The term is also used within the context of climate change to describe sudden climate change that is detectable over the time-scale of a human lifetime. Such a sudden climate change can be the result of feedback loops within the climate system or tipping points in the climate system.

Scientists may use different timescales when speaking of abrupt events. For example, the duration of the onset of the Paleocene–Eocene Thermal Maximum may have been anywhere between a few decades and several thousand years. In comparison, climate models predict that under ongoing greenhouse gas emissions, the Earth's near surface temperature could depart from the usual range of variability in the last 150 years as early as 2047.

Definitions

Abrupt climate change can be defined in terms of physics or in terms of impacts: "In terms of physics, it is a transition of the climate system into a different mode on a time scale that is faster than the responsible forcing. In terms of impacts, an abrupt change is one that takes place so rapidly and unexpectedly that human or natural systems have difficulty adapting to it. These definitions are complementary: the former gives some insight into how abrupt climate change comes about; the latter explains why there is so much research devoted to it."

Timescales

Timescales of events described as abrupt may vary dramatically. Changes recorded in the climate of Greenland at the end of the Younger Dryas, as measured by ice-cores, imply a sudden warming of +10 °C (+18 °F) within a timescale of a few years. Other abrupt changes are the +4 °C (+7.2 °F) on Greenland 11,270 years ago or the abrupt +6 °C (11 °F) warming 22,000 years ago on Antarctica.

By contrast, the Paleocene–Eocene Thermal Maximum may have initiated anywhere between a few decades and several thousand years. Finally, Earth System's models project that under ongoing greenhouse gas emissions as early as 2047, the Earth's near surface temperature could depart from the range of variability in the last 150 years.

Past events

The Younger Dryas period of abrupt climate change is named after the alpine flower, Dryas.

Several periods of abrupt climate change have been identified in the paleoclimatic record. Notable examples include:

• About 25 climate shifts, called Dansgaard–Oeschger cycles, which have been identified in the ice core record during the glacial period over the past 100,000 years.
• The Younger Dryas event, notably its sudden end. It is the most recent of the Dansgaard–Oeschger cycles and began 12,800 years ago and moved back into a warm-and-wet climate regime about 11,600 years ago."Abrupt Climate Change - What scientific evidence do we have that abrupt climate change has happened before?". ocp.ldeo.columbia.edu. It has been suggested that "the extreme rapidity of these changes in a variable that directly represents regional climate implies that the events at the end of the last glaciation may have been responses to some kind of threshold or trigger in the North Atlantic climate system." A model for this event based on disruption to the thermohaline circulation has been supported by other studies.
• The Paleocene–Eocene Thermal Maximum, timed at 55 million years ago, which may have been caused by the release of methane clathrates, although potential alternative mechanisms have been identified. This was associated with rapid ocean acidification
• The Permian–Triassic Extinction Event, in which up to 95% of all species became extinct, has been hypothesized to be related to a rapid change in global climate. Life on land took 30 million years to recover.
• The Carboniferous Rainforest Collapse occurred 300 million years ago, at which time tropical rainforests were devastated by climate change. The cooler, drier climate had a severe effect on the biodiversity of amphibians, the primary form of vertebrate life on land.

There are also abrupt climate changes associated with the catastrophic draining of glacial lakes. One example of this is the 8.2-kiloyear event, which is associated with the draining of Glacial Lake Agassiz. Another example is the Antarctic Cold Reversal, c. 14,500 years before present (BP), which is believed to have been caused by a meltwater pulse probably from either the Antarctic ice sheet or the Laurentide Ice Sheet. These rapid meltwater release events have been hypothesized as a cause for Dansgaard–Oeschger cycles.

A five-year study led by the Oxford School of Archaeology and additionally conducted by Royal Holloway, University of London, the Oxford University Museum of Natural History, and the National Oceanography Centre Southampton completed in 2013 called "Response of Humans to Abrupt Environmental Transitions" and referred to as "RESET" aimed to see if the hypothesis that humans have major development shifts during or immediately after abrupt climate changes with the aid of knowledge pulled from research on the palaeoenvironmental conditions, prehistoric archaeological history, oceanography, and volcanic geology of the last 130,000 years and across continents. It also aimed to predict possible human behavior in the event of climate change, and the timing of climate change.

A 2017 study concluded that similar conditions to today's Antarctic ozone hole (atmospheric circulation and hydroclimate changes), ~17,700 years ago, when stratospheric ozone depletion contributed to abrupt accelerated Southern Hemisphere deglaciation. The event coincidentally happened with an estimated 192-year series of massive volcanic eruptions, attributed to Mount Takahe in West Antarctica.

Possible precursors

Most abrupt climate shifts are likely due to sudden circulation shifts, analogous to a flood cutting a new river channel. The best-known examples are the several dozen shutdowns of the North Atlantic Ocean's Meridional Overturning Circulation during the last ice age, affecting climate worldwide.

• The current warming of the Arctic, the duration of the summer season, is considered abrupt and massive.
• Antarctic ozone depletion caused significant atmospheric circulation changes.
• There have also been two occasions when the Atlantic's Meridional Overturning Circulation lost a crucial safety factor. The Greenland Sea flushing at 75 °N shut down in 1978, recovering over the next decade. Then the second-largest flushing site, the Labrador Sea, shut down in 1997 for ten years. While shutdowns overlapping in time have not been seen during the 50 years of observation, previous total shutdowns had severe worldwide climate consequences.

It has been postulated that teleconnections – oceanic and atmospheric processes on different timescales – connect both hemispheres during abrupt climate change.

Climate feedback effects

The dark ocean surface reflects only 6 percent of incoming solar radiation; sea ice reflects 50 to 70 percent.

See also: Climate change feedback and Tipping points in the climate system

One source of abrupt climate change effects is a feedback process, in which a warming event causes a change that adds to further warming. The same can apply to cooling. Examples of such feedback processes are:

• Ice–albedo feedback in which the advance or retreat of ice cover alters the albedo ("whiteness") of the earth and its ability to absorb the sun's energy.
• Soil carbon feedback is the release of carbon from soils in response to global warming.
• The dying and the burning of forests by global warming.

The probability of abrupt change for some climate related feedbacks may be low. Factors that may increase the probability of abrupt climate change include higher magnitudes of global warming, warming that occurs more rapidly and warming that is sustained over longer time periods.

Tipping points in the climate system

Possible tipping elements in the climate system include regional effects of climate change, some of which had abrupt onset and may therefore be regarded as abrupt climate change. Scientists have stated, "Our synthesis of present knowledge suggests that a variety of tipping elements could reach their critical point within this century under anthropogenic climate change".

In climate science, a tipping point is a critical threshold that, when crossed, leads to large, accelerating and often irreversible changes in the climate system. If tipping points are crossed, they are likely to have severe impacts on human society and may accelerate global warming. Tipping behavior is found across the climate system, for example in ice sheets, mountain glaciers, circulation patterns in the ocean, in ecosystems, and the atmosphere. Examples of tipping points include thawing permafrost, which will release methane, a powerful greenhouse gas, or melting ice sheets and glaciers reducing Earth's albedo, which would warm the planet faster. Thawing permafrost is a threat multiplier because it holds roughly twice as much carbon as the amount currently circulating in the atmosphere.

Volcanism

Isostatic rebound in response to glacier retreat (unloading) and increased local salinity have been attributed to increased volcanic activity at the onset of the abrupt Bølling–Allerød warming. They are associated with the interval of intense volcanic activity, hinting at an interaction between climate and volcanism: enhanced short-term melting of glaciers, possibly via albedo changes from particle fallout on glacier surfaces.

Impacts

A summary of the path of the thermohaline circulation. Blue paths represent deep-water currents, and red paths represent surface currents.

The Permian–Triassic extinction event, labelled "P–Tr" here, is the most significant extinction event in this plot for marine genera.

In the past, abrupt climate change has likely caused wide-ranging and severe impacts as follows:

• Mass extinctions, most notably the Permian–Triassic extinction event (often referred colloquially to as the Great Dying) and the Carboniferous Rainforest Collapse, have been suggested as a consequence of abrupt climate change.
• Loss of biodiversity: without interference from abrupt climate change and other extinction events, the biodiversity of Earth would continue to grow.
• Sea ice decline in the North Atlantic and Nordic Seas, specifically in the Baffin Bay and Labrador Sea.
• Changes in ocean circulation such as:

• Increasing frequency of El Niño events
• Potential disruption to the thermohaline circulation, such as that which may have occurred during the Younger Dryas event.
• Changes to the North Atlantic oscillation.
• Changes in Atlantic meridional overturning circulation (AMOC) which could contribute to more severe weather events.

Placebo

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

Placebos are typically inert tablets, such as sugar pills.

A placebo (/pləˈsiːboʊ/ plə-SEE-boh) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.

Placebos are used in randomized clinical trials to test the efficacy of medical treatments. In a placebo-controlled trial, any change in the control group is known as the placebo response, and the difference between this and the result of no treatment is the placebo effect. Placebos in clinical trials should ideally be indistinguishable from so-called verum treatments under investigation, except for the latter's particular hypothesized medicinal effect. This is to shield test participants (with their consent) from knowing who is getting the placebo and who is getting the treatment under test, as patients' and clinicians' expectations of efficacy can influence results.

The idea of a "placebo effect" was discussed in 18th century psychology, but became more prominent in the 20th century. Modern studies find that placebos can affect some outcomes such as pain and nausea, but otherwise do not generally have important clinical effects. Improvements that patients experience after being treated with a placebo can also be due to unrelated factors, such as regression to the mean (a statistical effect where an unusually high or low measurement is likely to be followed by a less extreme one). The use of placebos in clinical medicine raises ethical concerns, especially if they are disguised as an active treatment, as this introduces dishonesty into the doctor–patient relationship and bypasses informed consent.

Placebos are also popular because they can sometimes produce relief through psychological mechanisms (a phenomenon known as the "placebo effect"). They can affect how patients perceive their condition and encourage the body's chemical processes for relieving pain and a few other symptoms, but have no impact on the disease itself.

Etymology and definition

The Latin term placebo means [I] shall be pleasing.

The definition of placebo has been debated. One definition states that a treatment process is a placebo when none of the characteristic treatment factors are effective (remedial or harmful) in the patient for a given disease.

In a clinical trial, a placebo response is the measured response of subjects to a placebo; the placebo effect is the difference between that response and no treatment. The placebo response may include improvements due to natural healing, declines due to natural disease progression, the tendency for people who were temporarily feeling either better or worse than usual to return to their average situations (regression toward the mean), and errors in the clinical trial records, which can make it appear that a change has happened when nothing has changed. It is also part of the recorded response to any active medical intervention.

Measurable placebo effects may be either objective (e.g. lowered blood pressure) or subjective (e.g. a lowered perception of pain).

Effects

"Placebo effect" redirects here. For other uses, see Placebo effect (disambiguation).

Further information: Alternative medicine § Perceived mechanism of effect

The placebo effect is a well-documented phenomenon, though it remains widely misunderstood and surrounded by misconceptions. Several studies have questioned its clinical relevance, fueling ongoing debate about its actual effectiveness. A 2001 meta-analysis of the placebo effect looked at trials in 40 different medical conditions, and concluded the only one where it had been shown to have a significant effect was for pain. Another Cochrane review in 2010 suggested that placebo effects are apparent only in subjective, continuous measures, and in the treatment of pain and related conditions. The review found that placebos do not appear to affect the actual diseases, or outcomes that are not dependent on a patient's perception. The authors, Asbjørn Hróbjartsson and Peter C. Gøtzsche, concluded that their study "did not find that placebo interventions have important clinical effects in general." This interpretation has been subject to criticism, particularly due to concerns about the adequacy of the methodology used. Recent research has linked placebo interventions to improved motor functions in patients with Parkinson's disease. Other objective outcomes affected by placebos include immune and endocrine parameters, end-organ functions regulated by the autonomic nervous system, and sport performance.

Measuring the extent of the placebo effect is difficult due to confounding factors. For example, a patient may feel better after taking a placebo due to regression to the mean (i.e. a natural recovery or change in symptoms), but this can be ruled out by comparing the placebo group with a no treatment group (as all the placebo research does). It is harder still to tell the difference between the placebo effect and the effects of response bias, observer bias and other flaws in trial methodology, as a trial comparing placebo treatment and no treatment will not be a blinded experiment. In their 2010 meta-analysis of the placebo effect, Asbjørn Hróbjartsson and Peter C. Gøtzsche argue that "even if there were no true effect of placebo, one would expect to record differences between placebo and no-treatment groups due to bias associated with lack of blinding."

One way in which the magnitude of placebo analgesia can be measured is by conducting "open/hidden" studies, in which some patients receive an analgesic and are informed that they will be receiving it (open), while others are administered the same drug without their knowledge (hidden). Such studies have found that analgesics are considerably more effective when the patient knows they are receiving them.

Factors influencing the power of the placebo effect

A review published in JAMA Psychiatry found that, in trials of antipsychotic medications, the change in response to receiving a placebo had increased significantly between 1960 and 2013. The review's authors identified several factors that could be responsible for this change, including inflation of baseline scores and enrollment of fewer severely ill patients. Another analysis published in Pain in 2015 found that placebo responses had increased considerably in neuropathic pain clinical trials conducted in the United States from 1990 to 2013. The researchers suggested that this may be because such trials have "increased in study size and length" during this time period.

Individual differences in personality traits may influence susceptibility to placebo and nocebo (negative placebo) effects. People with a more optimistic outlook tend to exhibit stronger placebo responses, while those with higher levels of anxiety are more likely to experience nocebo effects.

Children seem to have a greater response than adults to placebos.

The administration of the placebos can determine the placebo effect strength. Studies have found that taking more pills would strengthen the effect. Capsules appear to be more influential than pills, and injections are even stronger than capsules.

Some studies have investigated the use of placebos where the patient is fully aware that the treatment is inert, known as an open-label placebo. Clinical trials found that open-label placebos may have positive effects in comparison to no treatment, which may open new avenues for treatments, but a review of such trials noted that they were done with a small number of participants and hence should be interpreted with "caution" until further, better-controlled trials are conducted. An updated 2021 systematic review and meta-analysis based on 11 studies also found a significant, albeit slightly smaller overall effect of open-label placebos, while noting that "research on OLPs is still in its infancy."

If the person dispensing the placebo shows their care towards the patient, is friendly and sympathetic, or has a high expectation of a treatment's success, then the placebo is more effectual.

Depression

In 2008, a meta-analysis led by psychologist Irving Kirsch, analyzing data from the Food and Drug Administration (FDA), concluded that 82% of the response to antidepressants was accounted for by placebos. However, other authors expressed doubts about the used methods and the interpretation of the results, especially the use of 0.5 as the cut-off point for the effect size. A complete reanalysis and recalculation based on the same FDA data found that the Kirsch study had "important flaws in the calculations." The authors concluded that although a large percentage of the placebo response was due to expectancy, this was not true for the active drug. Besides confirming drug effectiveness, they found that the drug effect was not related to depression severity.

Another meta-analysis found that 79% of depressed patients receiving placebo remained well (for 12 weeks after an initial 6–8 weeks of successful therapy) compared to 93% of those receiving antidepressants. In the continuation phase however, patients on placebo relapsed significantly more often than patients on antidepressants.

Negative effects

Main article: Nocebo

A phenomenon opposite to the placebo effect has also been observed. When an inactive substance or treatment is administered to a recipient who has an expectation of it having a negative impact, this intervention is known as a nocebo (Latin nocebo = "I shall harm"). A nocebo effect occurs when the recipient of an inert substance reports a negative effect or a worsening of symptoms, with the outcome resulting not from the substance itself, but from negative expectations about the treatment.

Another negative consequence is that placebos can cause side-effects associated with real treatment.

Withdrawal symptoms can also occur after placebo treatment. This was found, for example, after the discontinuation of the Women's Health Initiative study of hormone replacement therapy for menopause. Women had been on placebo for an average of 5.7 years. Moderate or severe withdrawal symptoms were reported by 4.8% of those on placebo compared to 21.3% of those on hormone replacement.

Ethics

See also: Medical ethics and Philosophy of medicine

In research trials

Knowingly giving a person a placebo when there is an effective treatment available is a bioethically complex issue. While placebo-controlled trials might provide information about the effectiveness of a treatment, it denies some patients what could be the best available (if unproven) treatment. Informed consent is usually required for a study to be considered ethical, including the disclosure that some test subjects will receive placebo treatments.

The ethics of placebo-controlled studies have been debated in the revision process of the Declaration of Helsinki. Of particular concern has been the difference between trials comparing inert placebos with experimental treatments, versus comparing the best available treatment with an experimental treatment; and differences between trials in the sponsor's developed countries versus the trial's targeted developing countries.

Some suggest that existing medical treatments should be used instead of placebos, to avoid having some patients not receive medicine during the trial.

In medical practice

The practice of doctors prescribing placebos that are disguised as real medication is controversial. A chief concern is that it is deceptive and could harm the doctor–patient relationship in the long run. While some say that blanket consent, or the general consent to unspecified treatment given by patients beforehand, is ethical, others argue that patients should always obtain specific information about the name of the drug they are receiving, its side effects, and other treatment options. This view is shared by some on the grounds of patient autonomy. There are also concerns that legitimate doctors and pharmacists could open themselves up to charges of fraud or malpractice by using a placebo. Critics also argued that using placebos can delay the proper diagnosis and treatment of serious medical conditions.

Despite the abovementioned issues, 60% of surveyed physicians and head nurses reported using placebos in an Israeli study, with only 5% of respondents stating that placebo use should be strictly prohibited. A British Medical Journal editorial said, "that a patient gets pain relief from a placebo does not imply that the pain is not real or organic in origin ...the use of the placebo for 'diagnosis' of whether or not pain is real is misguided." A survey in the United States of more than 10,000 physicians came to the result that while 24% of physicians would prescribe a treatment that is a placebo simply because the patient wanted treatment, 58% would not, and for the remaining 18%, it would depend on the circumstances.

Referring specifically to homeopathy, the House of Commons of the United Kingdom Science and Technology Committee has stated:

In the Committee's view, homeopathy is a placebo treatment and the Government should have a policy on prescribing placebos. The Government is reluctant to address the appropriateness and ethics of prescribing placebos to patients, which usually relies on some degree of patient deception. Prescribing of placebos is not consistent with informed patient choice—which the Government claims is very important—as it means patients do not have all the information needed to make choice meaningful. A further issue is that the placebo effect is unreliable and unpredictable.

In his 2008 book Bad Science, Ben Goldacre argues that instead of deceiving patients with placebos, doctors should use the placebo effect to enhance effective medicines. Edzard Ernst has argued similarly that "As a good doctor you should be able to transmit a placebo effect through the compassion you show your patients." In an opinion piece about homeopathy, Ernst argues that it is wrong to support alternative medicine on the basis that it can make patients feel better through the placebo effect. His concerns are that it is deceitful and that the placebo effect is unreliable. Goldacre also concludes that the placebo effect does not justify alternative medicine, arguing that unscientific medicine could lead to patients not receiving prevention advice. Placebo researcher Fabrizio Benedetti also expresses concern over the potential for placebos to be used unethically, warning that there is an increase in "quackery" and that an "alternative industry that preys on the vulnerable" is developing.

Mechanisms

The mechanism for how placebos could have effects is uncertain. From a sociocognitive perspective, intentional placebo response is attributed to the "ritual effect" that induces anticipation for transition to a better state. A placebo presented as a stimulant may trigger an effect on heart rhythm and blood pressure, but when administered as a depressant, the opposite effect.

Psychology

The subjective effects of placebos may be related to expectations, yet similar effects have been noted in open-label studies.

In psychology, the two main hypotheses of the placebo effect are expectancy theory and classical conditioning.

In 1985, Irving Kirsch hypothesized that placebo effects are produced by the self-fulfilling effects of response expectancies, in which the belief that one will feel different leads a person to actually feel different. According to this theory, the belief that one has received an active treatment can produce the subjective changes thought to be produced by the real treatment. Similarly, the appearance of effect can result from classical conditioning, wherein a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the actual stimulus. Both conditioning and expectations play a role in placebo effect, and make different kinds of contributions. Conditioning has a longer-lasting effect, and can affect earlier stages of information processing. Those who think a treatment will work display a stronger placebo effect than those who do not, as evidenced by a study of acupuncture.

Additionally, motivation may contribute to the placebo effect. The active goals of an individual changes their somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues. Motivation may link to the meaning through which people experience illness and treatment. Such meaning is derived from the culture in which they live and which informs them about the nature of illness and how it responds to treatment.

Placebo analgesia

Functional imaging upon placebo analgesia suggests links to the activation, and increased functional correlation between this activation, in the anterior cingulate, prefrontal, orbitofrontal and insular cortices, nucleus accumbens, amygdala, the brainstem's periaqueductal gray matter, and the spinal cord.

Since 1978, it has been known that placebo analgesia depends upon the release of endogenous opioids in the brain. Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray on spinal nociceptive reflexes, while the expectations of anti-analgesic nocebos acts in the opposite way to block this.

Functional imaging upon placebo analgesia has been summarized as showing that the placebo response is "mediated by 'top-down' processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. Dopaminergic reward pathways may underlie these expectancies." "Diseases lacking major 'top-down' or cortically based regulation may be less prone to placebo-related improvement."

Brain and body

Further information: Neural top–down control of physiology

In conditioning, a neutral stimulus saccharin is paired in a drink with an agent that produces an unconditioned response. For example, that agent might be cyclophosphamide, which causes immunosuppression. After learning this pairing, the taste of saccharin by itself is able to cause immunosuppression, as a new conditioned response via neural top-down control. Such conditioning has been found to affect a diverse variety of not just basic physiological processes in the immune system but ones such as serum iron levels, oxidative DNA damage levels, and insulin secretion. Recent reviews have argued that the placebo effect is due to top-down control by the brain for immunity and pain. Pacheco-López and colleagues have raised the possibility of "neocortical-sympathetic-immune axis providing neuroanatomical substrates that might explain the link between placebo/conditioned and placebo/expectation responses." There has also been research aiming to understand underlying neurobiological mechanisms of action in pain relief, immunosuppression, Parkinson's disease and depression.

Dopaminergic pathways have been implicated in the placebo response in pain and depression.

Confounding factors

Placebo-controlled studies, as well as studies of the placebo effect itself, often fail to adequately identify confounding factors. False impressions of placebo effects are caused by many factors including:

• Regression to the mean (natural recovery or fluctuation of symptoms)
• Additional treatments
• Response bias from subjects, including scaling bias, answers of politeness, experimental subordination, conditioned answers;
• Reporting bias from experimenters, including misjudgment and irrelevant response variables.
• Non-inert ingredients of the placebo medication having an unintended physical effect

History

Main article: Placebo in history

A quack treating a patient with Perkins Patent Tractors by James Gillray, 1801. John Haygarth used this remedy to illustrate the power of the placebo effect.

The word placebo was used in a medicinal context in the late 18th century to describe a "commonplace method or medicine" and in 1811 it was defined as "any medicine adapted more to please than to benefit the patient." Although this definition contained a derogatory implication it did not necessarily imply that the remedy had no effect.

It was recognized in the 18th and 19th centuries that drugs or remedies often were perceived to work best while they were still novel:

We know that, in Paris, fashion imposes its dictates on medicine just as it does with everything else. Well, at one time, pyramidal elm bark had a great reputation; it was taken as a powder, as an extract, as an elixir, even in baths. It was good for the nerves, the chest, the stomach—what can I say?— it was a true panacea. At the peak of the fad, one of Bouvard's [sic] patients asked him if it might not be a good idea to take some: "Take it, Madame", he replied, "and hurry up while it [still] cures." [dépêchez-vous pendant qu'elle guérit]

— Gaston de Lévis quoting Michel-Philippe Bouvart in the 1780s

Placebos have featured in medical use until well into the twentieth century. An influential 1955 study entitled The Powerful Placebo firmly established the idea that placebo effects were clinically important, and were a result of the brain's role in physical health. A 1997 reassessment found no evidence of any placebo effect in the source data, as the study had not accounted for regression to the mean.

Placebo-controlled studies

Main article: Placebo-controlled study

The placebo effect makes it more difficult to evaluate new treatments. Clinical trials control for this effect by including a group of subjects that receives a sham treatment. The subjects in such trials are blinded as to whether they receive the treatment or a placebo. If a person is given a placebo under one name, and they respond, they will respond in the same way on a later occasion to that placebo under that name but not if under another.

Clinical trials are often double-blinded so that the researchers also do not know which test subjects are receiving the active or placebo treatment. The placebo effect in such clinical trials is weaker than in normal therapy since the subjects are not sure whether the treatment they are receiving is active.

Cultural influences

Anthropologists argue that culture affects the ways in which individuals perceive medication, from different rituals and methods of healing, leading to placebo. Hahn and Kleinman (1983) propose an "ethnomedicogenic thesis" of placebo, wherein the ethnomedical system generates a feedback loop: cultural beliefs influence the disease state produced and effective treatments reinforce the belief system.

"Symbolic effectiveness," a term coined by Claude Levi-Strauss relating to Shamanism, can result in a placebo effect as symbols displayed by the Shaman provide the patient with a form of "verbal expression" that can create a healing response within the patient. Apud and Romaní say that Shamans are a sort of psychoanalytical therapist, while many other cultural rituals and practices such as religion provide a psychological effect on the medical outcome of the patient, resulting in a placebo effect.

Hyland and Whalley conclude that carrying out a ritual, rather than believing in the ritual, may be an important factor in long-term placebo effects. One anthropological perspective of rituals describe them as repetitive activities that intend to provide a sense of significance to one's life, giving them a sense that their bodily experience is in the hands of the world, out of their control as a result of patterns and rules, external to their own body. Rituals are an attempt to "control nature," meaning that they can heal which results in the individual experience of placebo.