Acetylcholine

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Acetylcholine 

Chemical and physical data
Formula	C7H16NO2
Molar mass	146.210 g·mol−1

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

Acetylcholine is the neurotransmitter used at the neuromuscular junction. In other words, it is the chemical that motor neurons of the nervous system release in order to activate muscles. This property means that drugs that affect cholinergic systems can have very dangerous effects ranging from paralysis to convulsions. Acetylcholine is also a neurotransmitter in the autonomic nervous system, both as an internal transmitter for both the sympathetic and the parasympathetic nervous system, and as the final product released by the parasympathetic nervous system. Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system.

In the brain, acetylcholine functions as a neurotransmitter and as a neuromodulator. The brain contains a number of cholinergic areas, each with distinct functions; such as playing an important role in arousal, attention, memory and motivation. Acetylcholine has also been found in cells of non-neural origins as well as microbes. Recently, enzymes related to its synthesis, degradation and cellular uptake have been traced back to early origins of unicellular eukaryotes. The protist pathogens Acanthamoeba spp. have shown evidence of the presence of ACh, which provides growth and proliferative signals via a membrane-located M₁-muscarinic receptor homolog.

Partly because of acetylcholine's muscle-activating function, but also because of its functions in the autonomic nervous system and brain, many important drugs exert their effects by altering cholinergic transmission. Numerous venoms and toxins produced by plants, animals, and bacteria, as well as chemical nerve agents such as sarin, cause harm by inactivating or hyperactivating muscles through their influences on the neuromuscular junction. Drugs that act on muscarinic acetylcholine receptors, such as atropine, can be poisonous in large quantities, but in smaller doses they are commonly used to treat certain heart conditions and eye problems. Scopolamine, or diphenhydramine, which also act mainly on muscarinic receptors in an inhibitory fashion in the brain (especially the M₁ receptor) can cause delirium, hallucinations, and amnesia through receptor antagonism at these sites. So far as of 2016, only the M₁ receptor subtype has been implicated in anticholinergic delirium. The addictive qualities of nicotine are derived from its effects on nicotinic acetylcholine receptors in the brain.

Chemistry

Acetylcholine is a choline molecule that has been acetylated at the oxygen atom. Because of the charged ammonium group, acetylcholine does not penetrate lipid membranes. Because of this, when the molecule is introduced externally, it remains in the extracellular space and at present it is considered that the molecule does not pass through the blood–brain barrier.

Biochemistry

Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area is the nucleus basalis of Meynert in the basal forebrain. The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at the neuromuscular junction, causing paralysis of the muscles needed for breathing and stopping the beating of the heart.

Functions

Acetylcholine pathway.

Acetylcholine functions in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the CNS, cholinergic projections from the basal forebrain to the cerebral cortex and hippocampus support the cognitive functions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system.

Cellular effects

Main article: Acetylcholine receptor

Acetylcholine processing in a synapse. After release acetylcholine is broken down by the enzyme acetylcholinesterase.

Like many other biologically active substances, acetylcholine exerts its effects by binding to and activating receptors located on the surface of cells. There are two main classes of acetylcholine receptor, nicotinic and muscarinic. They are named for chemicals that can selectively activate each type of receptor without activating the other: muscarine is a compound found in the mushroom Amanita muscaria; nicotine is found in tobacco.

Nicotinic acetylcholine receptors are ligand-gated ion channels permeable to sodium, potassium, and calcium ions. In other words, they are ion channels embedded in cell membranes, capable of switching from a closed to an open state when acetylcholine binds to them; in the open state they allow ions to pass through. Nicotinic receptors come in two main types, known as muscle-type and neuronal-type. The muscle-type can be selectively blocked by curare, the neuronal-type by hexamethonium. The main location of muscle-type receptors is on muscle cells, as described in more detail below. Neuronal-type receptors are located in autonomic ganglia (both sympathetic and parasympathetic), and in the central nervous system.

Muscarinic acetylcholine receptors have a more complex mechanism, and affect target cells over a longer time frame. In mammals, five subtypes of muscarinic receptors have been identified, labeled M1 through M5. All of them function as G protein-coupled receptors, meaning that they exert their effects via a second messenger system. The M1, M3, and M5 subtypes are G_q-coupled; they increase intracellular levels of IP₃ and calcium by activating phospholipase C. Their effect on target cells is usually excitatory. The M2 and M4 subtypes are G_i/G_o-coupled; they decrease intracellular levels of cAMP by inhibiting adenylate cyclase. Their effect on target cells is usually inhibitory. Muscarinic acetylcholine receptors are found in both the central nervous system and the peripheral nervous system of the heart, lungs, upper gastrointestinal tract, and sweat glands.

Neuromuscular junction

Muscles contract when they receive signals from motor neurons. The neuromuscular junction is the site of the signal exchange. The steps of this process in vertebrates occur as follows: (1) The action potential reaches the axon terminal. (2) Calcium ions flow into the axon terminal. (3) Acetylcholine is released into the synaptic cleft. (4) Acetylcholine binds to postsynaptic receptors. (5) This binding causes ion channels to open and allows sodium ions to flow into the muscle cell. (6) The flow of sodium ions across the membrane into the muscle cell generates an action potential which induces muscle contraction. Labels: A: Motor neuron axon B: Axon terminal C: Synaptic cleft D: Muscle cell E: Part of a Myofibril

Main article: Neuromuscular junction

Acetylcholine is the substance the nervous system uses to activate skeletal muscles, a kind of striated muscle. These are the muscles used for all types of voluntary movement, in contrast to smooth muscle tissue, which is involved in a range of involuntary activities such as movement of food through the gastrointestinal tract and constriction of blood vessels. Skeletal muscles are directly controlled by motor neurons located in the spinal cord or, in a few cases, the brainstem. These motor neurons send their axons through motor nerves, from which they emerge to connect to muscle fibers at a special type of synapse called the neuromuscular junction.

When a motor neuron generates an action potential, it travels rapidly along the nerve until it reaches the neuromuscular junction, where it initiates an electrochemical process that causes acetylcholine to be released into the space between the presynaptic terminal and the muscle fiber. The acetylcholine molecules then bind to nicotinic ion-channel receptors on the muscle cell membrane, causing the ion channels to open. Sodium ions then flow into the muscle cell, initiating a sequence of steps that finally produce muscle contraction.

Factors that decrease release of acetylcholine (and thereby affecting P-type calcium channels):

1. Antibiotics (clindamycin, polymyxin)
2. Magnesium: antagonizes P-type calcium channels
3. Hypocalcemia
4. Anticonvulsants
5. Diuretics (furosemide)
6. Eaton-Lambert syndrome: inhibits P-type calcium channels
7. Myasthenia gravis
8. Botulinum toxin: inhibits SNARE proteins

Calcium channel blockers (nifedipine, diltiazem) do not affect P-channels. These drugs affect L-type calcium channels.

Autonomic nervous system

Components and connections of the parasympathetic nervous system.

The autonomic nervous system controls a wide range of involuntary and unconscious body functions. Its main branches are the sympathetic nervous system and parasympathetic nervous system. Broadly speaking, the function of the sympathetic nervous system is to mobilize the body for action; the phrase often invoked to describe it is fight-or-flight. The function of the parasympathetic nervous system is to put the body in a state conducive to rest, regeneration, digestion, and reproduction; the phrase often invoked to describe it is "rest and digest" or "feed and breed". Both of these aforementioned systems use acetylcholine, but in different ways.

At a schematic level, the sympathetic and parasympathetic nervous systems are both organized in essentially the same way: preganglionic neurons in the central nervous system send projections to neurons located in autonomic ganglia, which send output projections to virtually every tissue of the body. In both branches the internal connections, the projections from the central nervous system to the autonomic ganglia, use acetylcholine as a neurotransmitter to innervate (or excite) ganglia neurons. In the parasympathetic nervous system the output connections, the projections from ganglion neurons to tissues that do not belong to the nervous system, also release acetylcholine but act on muscarinic receptors. In the sympathetic nervous system the output connections mainly release noradrenaline, although acetylcholine is released at a few points, such as the sudomotor innervation of the sweat glands.

Direct vascular effects

Acetylcholine in the serum exerts a direct effect on vascular tone by binding to muscarinic receptors present on vascular endothelium. These cells respond by increasing production of nitric oxide, which signals the surrounding smooth muscle to relax, leading to vasodilation.

Central nervous system

Micrograph of the nucleus basalis (of Meynert), which produces acetylcholine in the CNS. LFB-HE stain.

In the central nervous system, ACh has a variety of effects on plasticity, arousal and reward. ACh has an important role in the enhancement of alertness when we wake up, in sustaining attention and in learning and memory.

Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be associated with the memory deficits associated with Alzheimer's disease. ACh has also been shown to promote REM sleep.

In the brainstem acetylcholine originates from the Pedunculopontine nucleus and laterodorsal tegmental nucleus collectively known as the mesopontine tegmentum area or pontomesencephalotegmental complex. In the basal forebrain, it originates from the basal nucleus of Meynert and medial septal nucleus:

• The pontomesencephalotegmental complex acts mainly on M1 receptors in the brainstem, deep cerebellar nuclei, pontine nuclei, locus coeruleus, raphe nucleus, lateral reticular nucleus and inferior olive. It also projects to the thalamus, tectum, basal ganglia and basal forebrain.
• Basal nucleus of Meynert acts mainly on M1 receptors in the neocortex.
• Medial septal nucleus acts mainly on M1 receptors in the hippocampus and parts of the cerebral cortex.

In addition, ACh acts as an important internal transmitter in the striatum, which is part of the basal ganglia. It is released by cholinergic interneurons. In humans, non-human primates and rodents, these interneurons respond to salient environmental stimuli with responses that are temporally aligned with the responses of dopaminergic neurons of the substantia nigra.

Memory

Acetylcholine has been implicated in learning and memory in several ways. The anticholinergic drug scopolamine impairs acquisition of new information in humans and animals. In animals, disruption of the supply of acetylcholine to the neocortex impairs the learning of simple discrimination tasks, comparable to the acquisition of factual information and disruption of the supply of acetylcholine to the hippocampus and adjacent cortical areas produces forgetfulness, comparable to anterograde amnesia in humans.

Diseases and disorders

Myasthenia gravis

The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces antibodies against acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission. Over time, the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine, physostigmine, or primarily pyridostigmine) are effective in treating the symptoms of this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the synaptic cleft (the space between nerve and muscle).

Pharmacology

Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it. Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand. Agonists increase the level of receptor activation; antagonists reduce it.

Acetylcholine itself does not have therapeutic value as a drug for intravenous administration because of its multi-faceted action (non-selective) and rapid inactivation by cholinesterase. However, it is used in the form of eye drops to cause constriction of the pupil during cataract surgery, which facilitates quick post-operational recovery.

Nicotinic receptors

Main article: Nicotinic receptor

Nicotine binds to and activates nicotinic acetylcholine receptors, mimicking the effect of acetylcholine at these receptors. ACh opens a Na⁺ channel upon binding so that Na⁺ flows into the cell. This causes a depolarization, and results in an excitatory post-synaptic potential. Thus, ACh is excitatory on skeletal muscle; the electrical response is fast and short-lived. Curares are arrow poisons, which act at nicotinic receptors and have been used to develop clinically useful therapies.

Muscarinic receptors

Main article: Muscarinic receptor

Muscarinic receptors form G protein-coupled receptor complexes in the cell membranes of neurons and other cells. Atropine is a non-selective competitive antagonist with Acetylcholine at muscarinic receptors.

Cholinesterase inhibitors

Main article: Cholinesterase inhibitors

Many ACh receptor agonists work indirectly by inhibiting the enzyme acetylcholinesterase. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system, which can result in fatal convulsions if the dose is high.

They are examples of enzyme inhibitors, and increase the action of acetylcholine by delaying its degradation; some have been used as nerve agents (Sarin and VX nerve gas) or pesticides (organophosphates and the carbamates). Many toxins and venoms produced by plants and animals also contain cholinesterase inhibitors. In clinical use, they are administered in low doses to reverse the action of muscle relaxants, to treat myasthenia gravis, and to treat symptoms of Alzheimer's disease (rivastigmine, which increases cholinergic activity in the brain).

Synthesis inhibitors

Organic mercurial compounds, such as methylmercury, have a high affinity for sulfhydryl groups, which causes dysfunction of the enzyme choline acetyltransferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function.

Release inhibitors

Botulinum toxin (Botox) acts by suppressing the release of acetylcholine, whereas the venom from a black widow spider (alpha-latrotoxin) has the reverse effect. ACh inhibition causes paralysis. When bitten by a black widow spider, one experiences the wastage of ACh supplies and the muscles begin to contract. If and when the supply is depleted, paralysis occurs.

Photopharmacological agents

Photopharmacology is an emerging field that uses light to control the activity of biologically active compounds with high spatial and temporal precision. Recent advances have applied this approach to the cholinergic system, including photoactivatable agonists and antagonists of muscarinic and nicotinic acetylcholine receptors, as well as light-sensitive acetylcholinesterase inhibitors, that enable reversible and targeted modulation of cholinergic signaling upon irradiation. These light-regulated compounds, based on either photolabile protecting groups ("caged" ligands) or photoisomerizable scaffolds, offer unprecedented control over acetylcholine-mediated processes and represent promising tools for both basic research and potential therapeutic applications.

Comparative biology and evolution

Acetylcholine is used by organisms in all domains of life for a variety of purposes. It is believed that choline, a precursor to acetylcholine, was used by single celled organisms billions of years ago for synthesizing cell membrane phospholipids. Following the evolution of choline transporters, the abundance of intracellular choline paved the way for choline to become incorporated into other synthetic pathways, including acetylcholine production. Acetylcholine is used by bacteria, fungi, and a variety of other animals. Many of the uses of acetylcholine rely on its action on ion channels via GPCRs like membrane proteins.

The two major types of acetylcholine receptors, muscarinic and nicotinic receptors, have convergently evolved to be responsive to acetylcholine. This means that rather than having evolved from a common homolog, these receptors evolved from separate receptor families. It is estimated that the nicotinic receptor family dates back longer than 2.5 billion years. Likewise, muscarinic receptors are thought to have diverged from other GPCRs at least 0.5 billion years ago. Both of these receptor groups have evolved numerous subtypes with unique ligand affinities and signaling mechanisms. The diversity of the receptor types enables acetylcholine to create varying responses depending on which receptor types are activated, and allow for acetylcholine to dynamically regulate physiological processes. ACh receptors are related to 5-HT3 (serotonin), GABA, and Glycine receptors, both in sequence and structure, strongly suggesting that they have a common evolutionary origin.

History

In 1867, Adolf von Baeyer resolved the structures of choline and acetylcholine and synthesized them both, referring to the latter as acetylneurin in the study. Choline is a precursor for acetylcholine. Acetylcholine was first noted to be biologically active in 1906, when Reid Hunt (1870–1948) and René de M. Taveau found that it decreased blood pressure in exceptionally tiny doses. This was after Frederick Walker Mott and William Dobinson Halliburton noted in 1899 that choline injections decreased the blood pressure of animals.

In 1914, Arthur J. Ewins was the first to extract acetylcholine from nature. He identified it as the blood pressure-decreasing contaminant from some Claviceps purpurea ergot extracts, by the request of Henry Hallett Dale. Later in 1914, Dale outlined the effects of acetylcholine at various types of peripheral synapses and also noted that it lowered the blood pressure of cats via subcutaneous injections even at doses of one nanogram.

The concept of neurotransmitters was unknown until 1921, when Otto Loewi noted that the vagus nerve secreted a substance that inhibited the heart muscle whilst working as a professor in the University of Graz. He named it vagusstoff ("vagus substance"), noted it to be a structural analog of choline and suspected it to be acetylcholine. In 1926, Loewi and E. Navratil deduced that the compound is probably acetylcholine, as vagusstoff and synthetic acetylcholine lost their activity in a similar manner when in contact with tissue lysates that contained acetylcholine-degrading enzymes (now known to be cholinesterases). This conclusion was accepted widely. Later studies confirmed the function of acetylcholine as a neurotransmitter.

Humorism

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Humorism

 

16th-century German illustration of the four humors: Flegmat (phlegm), Sanguin (blood), Coleric (yellow bile) and Melanc (black bile), divided between the male and female sexes

Humorism, the humoral theory, or humoralism, was a system of medicine detailing a supposed makeup and workings of the human body, adopted by Ancient Greek and Roman physicians and philosophers.

Humorism began to fall out of favor in the 17th century and it was definitively disproved with the discovery of microbes.

Origin

See also: Ancient Greek medicine

The concept of "humors" may have origins in Ancient Egyptian medicine, or Mesopotamia, though it was not systemized until ancient Greek thinkers. The word humor is a translation of Greek χυμός, chymos (literally 'juice' or 'sap', metaphorically 'flavor'). Early texts on Indian Ayurveda medicine presented a theory of three or four humors (doṣas), which they sometimes linked with the five elements (pañca-bhūta): earth, water, fire, air, and space.

The concept of "humors" (chemical systems regulating human behaviour) became more prominent from the writing of medical theorist Alcmaeon of Croton (c. 540–500 BC). His list of humors was longer and included fundamental elements described by Empedocles, such as water, earth, fire, air, etc. Hippocrates is usually credited with applying this idea to medicine. In contrast to Alcmaeon, Hippocrates suggested that humors are the vital bodily fluids: blood, phlegm, yellow bile, and black bile. Alcmaeon and Hippocrates posited that an extreme excess or deficiency of any of the humors (bodily fluid) in a person can be a sign of illness. Hippocrates, and then Galen, suggested that a moderate imbalance in the mixture of these fluids produces behavioral patterns. One of the treatises attributed to Hippocrates, On the Nature of Man, describes the theory as follows:

The Human body contains blood, phlegm, yellow bile, and black bile. These are the things that make up its constitution and cause its pains and health. Health is primarily that state in which these constituent substances are in the correct proportion to each other, both in strength and quantity, and are well mixed. Pain occurs when one of the substances presents either a deficiency or an excess, or is separated in the body and not mixed with others. The body depends heavily on the four humors because their balanced combination helps to keep people in good health. Having the right amount of humor is essential for health. The pathophysiology of disease is consequently brought on by humor excesses and/or deficiencies.

The existence of fundamental biochemical substances and structural components in the body remains a compellingly shared point with Hippocratic beliefs, despite the fact that current science has moved away from those four Hippocratic humors.

Although the theory of the four humors does appear in some Hippocratic texts, other Hippocratic writers accepted the existence of only two humors, while some refrained from discussing the humoral theory at all. Humoralism, or the doctrine of the four temperaments, as a medical theory retained its popularity for centuries, largely through the influence of the writings of Galen (129–201 AD). The four essential elements—humors—that make up the human body, according to Hippocrates, are in harmony with one another and act as a catalyst for preserving health. Hippocrates' theory of four humors was linked with the popular theory of the four elements (earth, fire, water, and air) proposed by Empedocles, but this link was not proposed by Hippocrates or Galen, who referred primarily to bodily fluids. While Galen thought that humors were formed in the body, rather than ingested, he believed that different foods had varying potential to act upon the body to produce different humors. Warm foods, for example, tended to produce yellow bile, while cold foods tended to produce phlegm. Seasons of the year, periods of life, geographic regions, and occupations also influenced the nature of the humors formed. As such, certain seasons and geographic areas were understood to cause imbalances in the humors, leading to varying types of disease across time and place. For example, cities exposed to hot winds were seen as having higher rates of digestive problems as a result of excess phlegm running down from the head, while cities exposed to cold winds were associated with diseases of the lungs, acute diseases, and "hardness of the bowels", as well as ophthalmies (issues of the eyes), and nosebleeds. Cities to the west, meanwhile, were believed to produce weak, unhealthy, pale people that were subject to all manners of disease. In the treatise, On Airs, Waters, and Places, a Hippocratic physician is described arriving to an unnamed city where they test various factors of nature including the wind, water, and soil to predict the direct influence on the diseases specific to the city based on the season and the individual.

A fundamental idea of Hippocratic medicine was the endeavor to pinpoint the origins of illnesses in both the physiology of the human body and the influence of potentially hazardous environmental variables like air, water, and nutrition, and every humor has a distinct composition and is secreted by a different organ. Aristotle's concept of eucrasia—a state resembling equilibrium—and its relationship to the right balance of the four humors allow for the maintenance of human health, offering a more mathematical approach to medicine.

The four humors as depicted in an 18th-century woodcut: phlegmatic, choleric, sanguine and melancholic

The imbalance of humors, or dyscrasia, was thought to be the direct cause of all diseases. Health was associated with a balance of humors, or eucrasia. The qualities of the humors, in turn, influenced the nature of the diseases they caused. Yellow bile caused warm diseases and phlegm caused cold diseases. In On the Temperaments, Galen further emphasized the importance of the qualities. An ideal temperament involved a proportionally balanced mixture of the four qualities. Galen identified four temperaments in which one of the qualities (warm, cold, moist, or dry) predominated, and four more in which a combination of two (warm and moist, warm and dry, cold and dry, or cold and moist) dominated. These last four, named for the humors with which they were associated—sanguine, choleric, melancholic and phlegmatic—eventually became better known than the others. While the term temperament came to refer just to psychological dispositions, Galen used it to refer to bodily dispositions, which determined a person's susceptibility to particular diseases, as well as behavioral and emotional inclinations.

Disease could also be the result of the "corruption" of one or more of the humors, which could be caused by environmental circumstances, dietary changes, or many other factors. These deficits were thought to be caused by vapors inhaled or absorbed by the body. Greeks and Romans, and the later Muslim and Western European medical establishments that adopted and adapted classical medical philosophy, believed that each of these humors would wax and wane in the body, depending on diet and activity. When a patient was suffering from a surplus or imbalance of one of the four humors, then said patient's personality and/or physical health could be negatively affected.

Therefore, the goal of treatment was to rid the body of some of the excess humor through techniques like purging, bloodletting, catharsis, diuresis, and others. Bloodletting was already a prominent medical procedure by the first century, but venesection took on even more significance once Galen of Pergamum declared blood to be the most prevalent humor. The volume of blood extracted ranged from a few drops to several litres over the course of several days, depending on the patient's condition and the doctor's practice.

Four humors

Even though humorism theory had several models that used two, three, and five components, the most famous model consists of the four humors described by Hippocrates and developed further by Galen. The four humors of Hippocratic medicine are black bile (Greek: μέλαινα χολή, melaina chole), yellow bile (Greek: ξανθὴ χολή, xanthe chole), phlegm (Greek: φλέγμα, phlegma), and blood (Greek: αἷμα, haima). Each corresponds to one of the traditional four temperaments. Based on Hippocratic medicine, it was believed that for a body to be healthy, the four humors should be balanced in amount and strength. The proper blending and balance of the four humors was known as eukrasia.

Humorism theory was improved by Galen, who incorporated his understanding of the humors into his interpretation of the human body. He believed the interactions of the humors within the body were the key to investigating the physical nature and function of the organ systems. Galen combined his interpretation of the humors with his collection of ideas concerning nature from past philosophers in order to find conclusions about how the body works. For example, Galen maintained the idea of the presence of the Platonic tripartite soul, which consisted of "thumos (spiritedness), epithumos (directed spiritedness, i.e. desire), and Sophia (wisdom)". Through this, Galen found a connection between these three parts of the soul and the three major organs that were recognized at the time: the brain, the heart, and the liver. This idea of connecting vital parts of the soul to vital parts of the body was derived from Aristotle's sense of explaining physical observations, and Galen utilized it to build his view of the human body. The organs (named organa) had specific functions (called chreiai) that contributed to the maintenance of the human body, and the expression of these functions is shown in characteristic activities (called energeiai) of a person. While the correspondence of parts of the body to the soul was an influential concept, Galen decided that the interaction of the four humors with natural bodily mechanisms were responsible for human development and this connection inspired his understanding of the nature of the components of the body.

Galen recalls the correspondence between humors and seasons in his On the Doctrines of Hippocrates and Plato, and says that, "As for ages and the seasons, the child (παῖς) corresponds to spring, the young man (νεανίσκος) to summer, the mature man (παρακµάζων) to autumn, and the old man (γέρων) to winter". He also related a correspondence between humors and seasons based on the properties of both. Blood, as a humor, was considered hot and wet. This gave it a correspondence to spring. Yellow bile was considered hot and dry, which related it to summer. Black bile was considered cold and dry, and thus related to autumn. Phlegm, cold and wet, was related to winter.

Galen also believed that the characteristics of the soul follow the mixtures of the body, but he did not apply this idea to the Hippocratic humors. He believed that phlegm did not influence character. In his On Hippocrates' The Nature of Man, Galen stated: "Sharpness and intelligence (ὀξὺ καὶ συνετόν) are caused by yellow bile in the soul, perseverance and consistency (ἑδραῖον καὶ βέβαιον) by the melancholic humor, and simplicity and naivety (ἁπλοῦν καὶ ἠλιθιώτερον) by blood. But the nature of phlegm has no effect on the character of the soul (τοῦ δὲ φλέγµατος ἡ φύσις εἰς µὲν ἠθοποιῗαν ἄχρηστος)." He further said that blood is a mixture of the four elements: water, air, fire, and earth.

These terms only partly correspond to modern medical terminology, in which there is no distinction between black and yellow bile, and phlegm has a very different meaning. It was believed that the humors were the basic substances from which all liquids in the body were made. Robin Fåhræus (1921), a Swedish physician who devised the erythrocyte sedimentation rate, suggested that the four humors were based upon the observation of blood clotting in a transparent container. When blood is drawn in a glass container and left undisturbed for about an hour, four different layers can be seen: a dark clot forms at the bottom (the "black bile"); above the clot is a layer of red blood cells (the "blood"); above this is a whitish layer of white blood cells (the "phlegm"); the top layer is clear yellow serum (the "yellow bile").

Many Greek texts were written during the golden age of the theory of the four humors in Greek medicine after Galen. One of those texts was an anonymous treatise called On the Constitution of the Universe and of Man, published in the mid-19th century by J. L. Ideler. In this text, the author establishes the relationship between elements of the universe (air, water, earth, fire) and elements of the man (blood, yellow bile, black bile, phlegm). He said that:

• The people who have red blood are friendly. They joke and laugh about their bodies, and they are rose-tinted, slightly red, and have pretty skin.
• The people who have yellow bile are bitter, short tempered, and daring. They appear greenish and have yellow skin.
• The people who are composed of black bile are lazy, fearful, and sickly. They have black hair and black eyes.
• Those who have phlegm are low spirited, forgetful, and have white hair.

Seventeenth century English playwright Ben Jonson wrote humor plays, where character types were based on their humoral complexion.

Blood

It was thought that the nutritional value of the blood was the source of energy for the body and the soul. Blood was believed to consist of small proportional amounts of the other three humors. This meant that taking a blood sample would allow for determination of the balance of the four humors in the body. It was associated with a sanguine nature (enthusiastic, active, and social). Blood is considered to be hot and wet, sharing these characteristics with the season of spring.

Yellow bile

Yellow bile was associated with a choleric nature (ambitious, decisive, aggressive, and short-tempered). It was thought to be fluid found within the gallbladder, or in excretions such as vomit and feces. The associated qualities for yellow bile are hot and dry with the natural association of summer and fire. It was believed that an excess of this humor in an individual would result in emotional irregularities such as increased anger or irrational behaviour.

Black bile

Black bile was associated with a melancholy nature, the word melancholy itself deriving from the Greek for 'black bile', μέλαινα χολή (melaina kholé). Depression was attributed to excess or unnatural black bile secreted by the spleen. Cancer was also attributed to an excess of black bile concentrated in a specific area. The seasonal association of black bile was to autumn as the cold and dry characteristics of the season reflect the nature of man.

Phlegm

Phlegm was associated with all phlegmatic nature, thought to be associated with reserved behavior. The phlegm of humorism is far from phlegm as it is defined today. Phlegm was used as a general term to describe white or colorless secretions such as pus, mucus, saliva, or sweat. Phlegm was also associated with the brain, possibly due to the color and consistency of brain tissue. The French physiologist and Nobel laureate Charles Richet, when describing humorism's "phlegm or pituitary secretion" in 1910, asked rhetorically, "this strange liquid, which is the cause of tumours, of chlorosis, of rheumatism, and cacochymia – where is it? Who will ever see it? Who has ever seen it? What can we say of this fanciful classification of humors into four groups, of which two are absolutely imaginary?" The seasonal association of phlegm is winter due to the natural properties of being cold and wet.

Humor production

Humors were believed to be produced via digestion as the final products of hepatic digestion. Digestion is a continuous process taking place in every animal, and it can be divided into four sequential stages. The gastric digestion stage, the hepatic digestion stage, the vascular digestion stage, and the tissue digestion stage. Each stage digests food until it becomes suitable for use by the body. In gastric digestion, food is made into chylous, which is suitable for the liver to absorb and carry on digestion. Chylous is changed into chymous in the hepatic digestion stage. Chymous is composed of the four humors: blood, phlegm, yellow bile, and black bile. These four humors then circulate in the blood vessels. In the last stage of digestion, tissue digestion, food becomes similar to the organ tissue for which it is destined.

If anything goes wrong leading up to the production of humors, there will be an imbalance leading to disease. Proper organ functioning is necessary in the production of good humor. The stomach and liver also have to function normally for proper digestion. If there are any abnormalities in gastric digestion, the liver, blood vessels, and tissues cannot be provided with the raw chylous, which can cause abnormal humor and blood composition. A healthy functioning liver is not capable of converting abnormal chylous into normal chylous and normal humors.

Humors are the end product of gastric digestion, but they are not the end product of the digestion cycle, so an abnormal humor produced by hepatic digestion will affect other digestive organs.

Relation to jaundice

According to Hippocratic humoral theory, jaundice is present in the Hippocratic Corpus. Some of the first descriptions of jaundice come from the Hippocratic physicians (icterus). The ailment appears multiple times in the Hippocratic Corpus, where its genesis, description, prognosis, and therapy are given. The five kinds of jaundice mentioned in the Hippocratic Corpus all share a yellow or greenish skin color.

A modern doctor will undoubtedly start to think of the symptoms listed in contemporary atlases of medicine after reading the clinical symptoms of each variety of jaundice listed in the Hippocratic Corpus. Despite the fact that the Hippocratic physicians' therapeutic approaches have little to do with contemporary medical practice, their capacity for observation as they described the various forms of jaundice is remarkable. In the Hippocratic Corpus, the Hippocratic physicians make multiple references to jaundice. At that time, jaundice was viewed as an illness unto itself rather than a symptom brought on by a disease.

Unification with Empedocles's model

Empedocles's theory suggested that there are four elements: earth, fire, water, and air, with the earth producing the natural systems. Since this theory was influential for centuries, later scholars paired qualities associated with each humor as described by Hippocrates/Galen with seasons and "basic elements" as described by Empedocles.

The following table shows the four humors with their corresponding elements, seasons, sites of formation, and resulting temperaments:

Humor	Season	Age	Element	Organ	Temperaments
Blood	Spring	Infancy	Air	Liver	Warm and moist	Sanguine
Yellow bile	Summer	Youth	Fire	Gallbladder	Warm and dry	Choleric
Black bile	Autumn	Adulthood	Earth	Spleen	Cold and dry	Melancholic
Phlegm	Winter	Old age	Water	Brain/Lungs	Cold and moist	Phlegmatic

Influence and legacy

Islamic medicine

See also: Medicine in medieval Islam and Unani

Medieval medical tradition in the Golden Age of Islam adopted the theory of humorism from Greco-Roman medicine, notably via the Persian polymath Avicenna's The Canon of Medicine (1025). Avicenna summarized the four humors and temperaments as follows:

Avicenna's (ibn Sina) four humors and temperaments

Evidence	Hot	Cold	Moist	Dry
Morbid states	Inflammations become febrile	Fevers related to serious humor, rheumatism	Lassitude	Loss of vigour
Functional power	Deficient energy	Deficient digestive power	Difficult digestion
Subjective sensations	Bitter taste, excessive thirst, burning at cardia	Lack of desire for fluids	Mucoid salivation, sleepiness	Insomnia, wakefulness
Physical signs	High pulse rate, lassitude	Flaccid joints	Diarrhea, swollen eyelids, rough skin, acquired habit	Rough skin, acquired habit
Foods and medicines	Calefacients harmful, infrigidants beneficial	Infrigidants harmful, calefacients beneficial	Moist articles harmful	Dry regimen harmful, humectants beneficial
Relation to weather	Worse in summer	Worse in winter		Bad in autumn

Perso-Arabic and Indian medicine

The Unani school of medicine, practiced in Perso-Arabic countries, India, and Pakistan, is based on Galenic and Avicennian medicine in its emphasis on the four humors as a fundamental part of the methodologic paradigm.

Western medicine

The humoralist system of medicine was highly individualistic, for all patients were said to have their own unique humoral composition. From Hippocrates onward, the humoral theory was adopted by Greek, Roman and Islamic physicians, and dominated the view of the human body among European physicians until at least 1543 when it was first seriously challenged by Andreas Vesalius, who mostly criticized Galen's theories of human anatomy and not the chemical hypothesis of behavioural regulation (temperament).

The four humors and their qualities

Typical 18th-century practices such as bleeding a sick person or applying hot cups to a person were based on the humoral theory of imbalances of fluids (blood and bile in those cases). Methods of treatment like bloodletting, emetics and purges were aimed at expelling a surplus of a humor. Apocroustics were medications intended to stop the flux of malignant humors to a diseased body part.

16th-century Swiss physician Paracelsus further developed the idea that beneficial medical substances could be found in herbs, minerals and various alchemical combinations thereof. These beliefs were the foundation of mainstream Western medicine well into the 17th century. Specific minerals or herbs were used to treat ailments simple to complex, from an uncomplicated upper respiratory infection to the plague. For example, chamomile was used to decrease heat, and lower excessive bile humor. Arsenic was used in a poultice bag to 'draw out' the excess humor(s) that led to symptoms of the plague. Apophlegmatisms, in pre-modern medicine, were medications chewed in order to draw away phlegm and humors.

Although advances in cellular pathology and chemistry criticized humoralism by the 17th century, the theory had dominated Western medical thinking for more than 2,000 years. Only in some instances did the theory of humoralism wane into obscurity. One such instance occurred in the sixth and seventh centuries in the Byzantine Empire when traditional secular Greek culture gave way to Christian influences. Though the use of humoralist medicine continued during this time, its influence was diminished in favor of religion. The revival of Greek humoralism, owing in part to changing social and economic factors, did not begin until the early ninth century. Use of the practice in modern times is pseudoscience.

Modern use

Humoral theory was the grand unified theory of medicine, before the invention of modern medicine, for more than 2,000 years. The theory was one of the fundamental tenets of the teachings of the Greek physician-philosopher Hippocrates (460–370 BC), who is regarded as the first practitioner of medicine, appropriately referred to as the "Father of Modern Medicine".

With the advent of the Doctrine of Specific Etiology, the humoral theory's demise hastened even further. This demonstrates that there is only one precise cause and one specific issue for each and every sickness or disorder that has been diagnosed. Additionally, the identification of messenger molecules like hormones, growth factors, and neurotransmitters suggests that the humoral theory has not yet been made fully moribund. Humoral theory is still present in modern medical terminology, which refers to humoral immunity when discussing elements of immunity that circulate in the bloodstream, such as hormones and antibodies.

Modern medicine refers to humoral immunity or humoral regulation when describing substances such as hormones and antibodies, but this is not a remnant of the humor theory. It is merely a literal use of humoral, i.e. pertaining to bodily fluids (such as blood and lymph).

The concept of humorism was not definitively disproven until 1858. There were no studies performed to prove or disprove the impact of dysfunction in known bodily organs producing named fluids (humors) on temperament traits simply because the list of temperament traits was not defined up until the end of the 20th century.

Culture

Theophrastus and others developed a set of characters based on the humors. Those with too much blood were sanguine. Those with too much phlegm were phlegmatic. Those with too much yellow bile were choleric, and those with too much black bile were melancholic. The idea of human personality based on humors contributed to the character comedies of Menander and, later, Plautus. Through the neo-classical revival in Europe, the humor theory dominated medical practice, and the theory of humoral types made periodic appearances in drama. The humors were an important and popular iconographic theme in European art, found in paintings, tapestries, and sets of prints.

The humors can be found in Elizabethan works, such as in The Taming of the Shrew, in which the character Petruchio, a choleric man, uses humoral therapy techniques on Katherina, a choleric woman, in order to tame her into the socially acceptable phlegmatic woman. Some examples include: he yells at the servants for serving mutton, a choleric food, to two people who are already choleric; he deprives Katherina of sleep; and he, Katherina and their servant Grumio endure a cold walk home, for cold temperatures were said to tame choleric temperaments.

The theory of the four humors features prominently in Rupert Thomson's 2005 novel Divided Kingdom.

Endless Forms Most Beautiful (book)

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Endless_Forms_Most_Beautiful_(book) 

 

Endless Forms Most Beautiful

Author	Sean B. Carroll
Subject	Evolutionary developmental biology (evo-devo)
Genre	Popular science
Publisher	W. W. Norton
Publication date	2005
Publication place	USA
Pages	331

Endless Forms Most Beautiful: The New Science of Evo Devo and the Making of the Animal Kingdom is a 2005 book by the molecular biologist Sean B. Carroll. It presents a summary of the emerging field of evolutionary developmental biology and the role of toolkit genes. It has won numerous awards for science communication.

The book's somewhat controversial argument is that evolution in animals (though no doubt similar processes occur in other organisms) proceeds mostly by modifying the way that regulatory genes, which do not code for structural proteins (such as enzymes), control embryonic development. In turn, these regulatory genes turn out to be based on a very old set of highly conserved genes which Carroll nicknames the toolkit. Almost identical sequences can be found across the animal kingdom, meaning that toolkit genes such as Hox must have evolved before the Cambrian radiation which created most of the animal body plans that exist today. These genes are used and reused, occasionally by duplication but far more often by being applied unchanged to new functions. Thus the same signal may be given at a different time in development, in a different part of the embryo, creating a different effect on the adult body. In Carroll's view, this explains how so many body forms are created with so few structural genes.

The book has been praised by critics, and called the most important popular science book since Richard Dawkins's The Blind Watchmaker.

Author

Sean B. Carroll in 2008

Sean B. Carroll is a professor of molecular biology and genetics at the University of Wisconsin–Madison. He studies the evolution of cis-regulatory elements (pieces of non-coding DNA) which help to regulate gene expression in developing embryos, using the fruit fly Drosophila as the model organism. He has won the Shaw Scientist Award and the Stephen Jay Gould Prize for his work.

Book

Context

Further information: Evolutionary developmental biology

The book's title quotes from the last sentence of Charles Darwin's 1859 The Origin of Species, in which he described the evolution of all living organisms from a common ancestor: "endless forms most beautiful and most wonderful have been, and are being, evolved." Darwin, however, was unable to explain how those body forms actually came into being. The early 20th-century modern synthesis of evolution and genetics, too, largely ignored embryonic development to explain the form of organisms, since population genetics appeared to be an adequate explanation of how forms evolved. That task was finally undertaken at the end of the 20th century with the arrival of recombinant DNA technology, when biologists were able to start to explore how development was actually controlled.

Contents

The body of a trilobite is made of many similar modules (body segments with pairs of appendages). These could be made by repeated use of the same toolkit genes.

Part I The Making of Animals

1. Animal Architecture: Modern Forms, Ancient Designs

Carroll argues that many animals have a modular design with repeated parts, as in trilobites with repeated segments, or the repeated fingers of a human hand.

2. Monsters, Mutants, and Master Genes

Embryologists study how bodies develop, and the abnormalities when things go wrong, such as homeotic variants when one body part is changed into another (for instance, a fruit fly antenna becomes a leg with the Antennapedia mutant).

3. From E. coli to Elephants

This chapter tells the tale of the genetic code, and the lac operon, showing that the environment and genetic switches together control gene expression. He introduces the evo-devo gene toolkit.

4. Making Babies: 25,000 Genes, Some Assembly Required

Carroll looks at how a fruit fly's embryonic development is controlled and describes his own discoveries (back in 1994).

5. The Dark Matter of the Genome: Operating Instructions for the Tool Kit

The chapter describes how genes are switched on and off in a precisely choreographed time sequence and 3-dimensional pattern in the developing embryo and how the logic can be modified by evolution to create different animal bodies.

Crayfish limbs are highly specialised, adapted by evo-devo gene toolkit changes from the simple appendages of their trilobite-like ancestors.

This fruit fly embryo is stained to show the expression of some of the genes (named) that control its development.

Part II Fossils, Genes, and the Making of Animal Diversity

6. The Big Bang of Animal Evolution

The Cambrian radiation saw an explosion in the variety of animal body plans, from flatworms and molluscs to arthropods and vertebrates. Carroll explains how shifting the pattern of Hox gene expression shaped the bodies of different types of arthropods and different types of vertebrates.

7. Little Bangs: Wings and Other Revolutionary Inventions

This chapter explains how evolution goes to work within a lineage, specialising arthropod limbs from all being alike to "all of the different implements a humble crayfish carries", with (he writes) more gizmos than a Swiss Army knife.

8. How the Butterfly Got Its Spots

Echoing the titles of Rudyard Kipling's Just So Stories, Carroll shows how butterfly wing patterns evolved, including his discovery of the role of the Distal-less gene there, until then known in limb development. Evidently, a genetic switch could be reused for different purposes.

9. Paint It Black

Carroll looks at zebra stripes, industrial melanism in the peppered moth and the spots of big cats, all examples of the control of pattern in animals, down to molecular level.

10. A Beautiful Mind: The Making of Homo sapiens.

This chapter discusses how humans differ from other apes and why there are not many structural genes for the differences. Most of the changes are in genetic control, not in proteins.

11. Endless Forms Most Beautiful

Carroll concludes by revisiting Darwin's Origin of Species, starting with how Darwin evolved the final paragraph of his book, leaving only these four words "completely untouched throughout all versions and editions". He shows that evo-devo is a cornerstone of a synthesis of evolution, genetics, and embryology, replacing the "Modern synthesis" of 20th century biology.

Illustrations

The book is illustrated with photographs, such as of developing fruit fly embryos dyed to show the effects of toolkit genes, and with line drawings by Jamie W. Carroll, Josh P. Klaiss and Leanne M. Olds.

Awards

• Discover magazine's Top Science Books of the Year, 2005
• USA Today's Top Science Books of the Year, 2005
• Banta Prize, Wisconsin Library Association, 2006
• Finalist, 2005 Los Angeles Times Book Prize (Science and Technology)
• Finalist, 2006 National Academy of Sciences Communication Award

Reception

"Kipling would be riveted": the book explains how animals actually acquired the features that Rudyard Kipling wrote about in his 1902 Just So Stories, such as "How the Elephant got his Trunk".

The evolutionary biologist Lewis Wolpert, writing in American Scientist, called Endless Forms Most Beautiful "a beautiful and very important book." He summarized the message of the book with the words "As Darwin's theory made clear, these multitudinous forms developed as a result of small changes in offspring and natural selection of those that were better adapted to their environment. Such variation is brought about by alterations in genes that control how cells in the developing embryo behave. Thus one cannot understand evolution without understanding its fundamental relation to development of the embryo." Wolpert noted that Carroll intended to explain evo-devo, and "has brilliantly achieved what he set out to do."

The evolutionary biologist Jerry Coyne, writing in Nature, described the book as for the interested lay reader, and called it "a paean to recent advances in developmental genetics, and what they may tell us about the evolutionary process." For him, the centrepiece was "the unexpected discovery that the genes that control the body plans of all bilateral animals, including worms, insects, frogs and humans, are largely identical. These are the 'homeobox' (Hox) genes". He called Carroll a leader in the field and an "adept communicator", but admits to "feeling uncomfortable" when Carroll sets out his personal vision of the field "without admitting that large parts of that vision remain controversial." Coyne pointed out that the idea that the "'regulatory gene' is the locus of evolution" dates back to Roy Britten and colleagues around 1970, but was still weakly supported by observation or experiment. He granted that chimps and humans are almost 99% identical at DNA level, but points out that "humans and chimps have different amino-acid sequences in at least 55% of their proteins, a figure that rises to 95% for humans and mice. Thus we can't exclude protein-sequence evolution as an important reason why we lack whiskers and tails." He also noted that nearly half of human protein-coding genes do not have homologues in fruit flies, so one could argue the opposite of Carroll's thesis and claim that "evolution of form is very much a matter of teaching old genes to make new genes."

The review in BioScience noted that the book serves as a new Just So Stories, explaining the "spots, stripes, and bumps" that had attracted Rudyard Kipling's attention in his children's stories. The review praised Carroll for tackling human evolution and covering the key concepts of what Charles Darwin called the grandeur of [the evolutionary view of] life, suggesting that "Kipling would be riveted."

The science writer Peter Forbes, writing in The Guardian, called it an "essential book" and its author "both a distinguished scientist ... and one of our great science writers." The journalist Dick Pountain, writing in PC Pro magazine, argued that Endless Forms Most Beautiful was the most important popular science book since Richard Dawkins's The Blind Watchmaker, "and in effect a sequel [to it]."

The paleobiologist Douglas H. Erwin, reviewing the book for Artificial Life, noted that life forms from fruit flies to humans have far fewer genes than many biologists expected – human beings have only some 20,000. "How could humans, in all our diversity of cell types and complexity of neurons, require essentially the same number of genes as a fly, or worse, a worm (the nematode Caenorhabditis elegans)?" asks Erwin. He answered his own question about the "astonishing morphological diversity" of animals coming from "such a limited number of genes", praising Carroll's "insightful and enthusiastic" style, writing in a "witty and engaging" way, pulling the reader into the complexities of Hox and PAX-6, as well as celebrating the Cambrian explosion of life forms and much else.