Wet nurse

From Wikipedia, the free encyclopedia

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

Louis XIV as an infant with his nurse Longuet de la Giraudière

A wet nurse is a woman who breastfeeds and cares for another's child. Wet nurses are employed if the mother dies, or if she is unable or chooses not to nurse the child herself. Wet-nursed children may be known as "milk-siblings", and in some cultures, the families are linked by a special relationship of milk kinship. Wet-nursing existed in cultures around the world until the invention of reliable formula milk in the 20th century. The practice has made a small comeback in the 21st century.

Reasons

A wet nurse can help when a mother is unable or unwilling to breastfeed her baby. Before the development of infant formula in the 20th century, wet-nursing could save a baby's life.

There are many reasons why a mother is unable to produce sufficient breast milk, or in some cases to lactate at all. For example, she may have a chronic or acute illness, and either the illness itself, or the treatment for it, reduces or stops her milk. This absence of lactation may be temporary or permanent.

There was a greater need for wet nurses when the rates of infant abandonment and maternal death, during and shortly after childbirth, were high. There was a concurrent availability of lactating women whose own babies had died.

Some women chose not to breastfeed for social reasons. For upper-class women, breastfeeding was considered unfashionable, in the sense that it not only prevented them from being able to wear the fashionable clothing of their time, but it was also thought to ruin their figures. Working women faced other pressures to abandon breastfeeding, including from their husbands. Hiring a wet nurse was less expensive than having to hire someone else to help run the family business and/or take care of the family household duties in their place. Some women chose to hire wet nurses purely to escape from the confining and time-consuming chore of breastfeeding. Wet nurses have also been used when a mother cannot produce sufficient breast milk.

Eliciting milk

A 16th-century carving in a Belgian church, showing a woman expressing her milk into a bowl.

A woman can only act as a wet nurse if she is lactating (producing milk). It was once believed that a wet nurse must have recently undergone childbirth in order to lactate. This is not necessarily the case, as regular breast stimulation can elicit lactation via a neural reflex of prolactin production and secretion. Some women have been able to establish lactation using a breast pump, in order to feed an infant.

Gabrielle Palmer, author of The Politics of Breastfeeding, states:

There is no medical reason why women should not lactate indefinitely or feed more than one child simultaneously (known as 'tandem feeding')...some women could theoretically be able to feed up to five babies.

Historical and cultural practices

A Russian wet nurse, c. 1913

Wet nursing is an ancient practice, common to many cultures. It has been linked to social class, where monarchies, the aristocracy, nobility, or upper classes had their children wet-nursed for the benefit of the child's health, and sometimes in the hope of becoming pregnant again quickly. Exclusive breastfeeding inhibits ovulation in some women (lactational amenorrhea). Poor women, especially those who suffered the stigma of giving birth to an illegitimate child, sometimes had to give their baby up temporarily to a wet nurse, or permanently to another family. The woman herself might in turn become wet nurse to a wealthier family, while using part of her wages to pay her own child's wet nurse. From Roman times and into the present day, philosophers and thinkers alike have held the view that the important emotional bond between mother and child is threatened by the presence of a wet nurse.

In pre-modern times, it was incorrectly believed that wet nurses could pass on personality traits to infants, such as acquired characteristics.

Mythology

Many cultures feature stories, historical or mythological, involving superhuman, supernatural, human, and in some instances, animal wet nurses.

The Bible refers to Deborah, a nurse to Rebekah, wife of Isaac and mother of Jacob (Israel) and Esau, who appears to have lived as a member of the household all her days. (Genesis 35:8.) Midrashic commentaries on the Torah hold that the Egyptian princess Bithiah (Pharaoh's wife Asiya in the Islamic Hadith and Qur'an) attempted to wet-nurse Moses, but he would take only his biological mother's milk. (Exodus 2:6–9)

In Greek mythology, Eurycleia is the wet nurse of Odysseus. In Roman mythology, Caieta was the wet nurse of Aeneas. In Burmese mythology, Myaukhpet Shinma is the nat (spirit) representation of the wet nurse of King Tabinshwehti. In Hawaiian mythology, Nuakea is a beneficent goddess of lactation; her name became the title for a royal wet nurse, according to David Malo.

Ancient Rome

A funerary stele (akin to a gravestone) erected by Roman citizen Lucius Nutrius Gallus in the 2nd half of the 1st century AD for himself, his wet nurse, and other members of his family and household

In ancient Rome, well-to-do households would have had wet nurses (Latin nutrices, singular nutrix) among their slaves and freedwomen, but some Roman women were wet nurses by profession, and the Digest of Roman law even refers to a wage dispute for wet-nursing services (nutricia). The landmark known as the Columna Lactaria ("Milk Column") may have been a place where wet nurses could be hired. It was considered admirable for upperclass women to breastfeed their own children, but unusual and old-fashioned in the Imperial era. Even women of the working classes or slaves might have their babies nursed, and the Roman-era Greek gynecologist Soranus offers detailed advice on how to choose a wet nurse. Inscriptions such as religious dedications and epitaphs indicate that a nutrix would be proud of her profession. One even records a nutritor lactaneus, a male "milk nurse" who presumably used a bottle. Greek nurses were preferred, and the Romans believed that a baby who had a Greek nutrix could imbibe the language and grow up speaking Greek as fluently as Latin.

The importance of the wet nurse to ancient Roman culture is indicated by the founding myth of Romulus and Remus, who were abandoned as infants but nursed by the she-wolf, as portrayed in the famous Capitoline Wolf bronze sculpture. The goddess Rumina was invoked among other birth and child development deities to promote the flow of breast milk.

India

By the 1500s, a wealthy mother who did not use a wet nurse was worthy of remark in India. The child was not "put out" of the household; rather, the wet nurse was included within it. The imperial wet nurses of the Mughal court were given honours in the Turco-Mongol tradition.

United Kingdom

Catherine Willoughby, formerly Duchess of Suffolk, and her later husband Richard Bertie, are forced into exile, taking their baby and wet nurse

Wet nursing used to be commonplace in the United Kingdom. Working-class women both provided and received wet-nursing services.

Taking care of babies was a well-paid, respectable, and popular job for many working-class women. In the 18th century, a woman would earn more money as a wet nurse than an average man could as a labourer. Up until the 19th century, most wet-nursed infants were sent far from their families to live with their new caregiver for up to the first three years of their life. As many as 80% of wet-nursed babies who lived like this died during infancy.

During the Victorian era, women took in babies for money and nursed them themselves or fed them with whatever was cheapest. This was known as baby-farming; poor care sometimes resulted in high infant death rates. The wet nurse at this period was most likely a single woman who previously had given birth to an illegitimate child. There were two types of wet nurses by this time: those on poor relief, who struggled to provide sufficiently for themselves or their charges, and the professionals, who were well paid and respected.

Upper-class women tended to hire wet nurses to work within their own homes, as part of a large household of servants.

Wet nurses also worked at foundling hospitals, establishments for abandoned children. Their own children would likely be sent away, normally brought up by the bottle rather than being breastfed. Valerie Fildes, author of Breasts, Bottle and Babies: A History of Infant Feeding, argues that "In effect, wealthy parents frequently 'bought' the life of their infant for the life of another."

Wet nursing decreased in popularity during the mid-19th century, as medical journalists wrote about its previously undocumented dangers. Fildes argued that "Britain has been lumped together with the rest of Europe in any discussion of the qualities, terms of employment and conditions of the wet nurse, and particularly the abuses of which she was supposedly guilty." C. H. F. Routh, a medical journalist writing in the late 1850s, listed the evils of wet nursing, such as the abandonment of the wet nurses' own children, higher infant mortality, and an increased physical and moral risk to a nursed child. While this argument was not founded in any sort of proof, the emotional arguments of medical researchers, coupled with the protests of other critics, slowly increased public knowledge; the practice declined, replaced by maternal breastfeeding and bottle-feeding.

France

The bureau of wet nurses in Paris

See also: Selling Mother's Milk: The Wet-Nursing Business in France, 1715–1914

Wet-nursing was reported in France in the time of Louis XIV, the mid-17th century. By the 18th century, approximately 90% of infants were wet-nursed, mostly sent away to live with their wet nurses. In Paris, only 1,000 of the 21,000 babies born in 1780 were nursed by their own mothers. The high demand for wet nurses coincided with the low wages and high rent prices of this era, which forced many women to have to work soon after childbirth. This meant that many mothers had to send their infants away to be breastfed and cared for by wet nurses even poorer than themselves. With the high demand for wet nurses, the price to hire one increased as the standard of care decreased. This led to many infant deaths. In response, rather than nursing their own children, upper-class women turned to hiring wet nurses to come live with them instead. In entering into their employer's home to care for their charges, these wet nurses had to leave their own infants to be nursed and cared for by women far worse off than themselves, and who likely lived at a relatively far distance away.

The Bureau of Wet Nurses was created in Paris in 1769 to serve two main purposes: it supplied parents with wet nurses, as well as helping lessen the neglect of babies by controlling monthly salary payments. In order to become a wet nurse, women had to meet a few qualifications, including physical fitness and good moral character; they were often judged on their age, their health, the number of children they had, as well as their breast shape, breast size, breast texture, nipple shape, and nipple size, since all these aspects were believed to affect the quality of a woman's milk. In 1874, the French government introduced a law named after Dr. Theophile Roussel, which "mandated that every infant placed with a paid guardian outside the parents' home be registered with the state so that the French government is able to monitor how many children are placed with wet nurses and how many wet-nursed children have died".

Wet nurses were hired to work in hospitals to nurse babies who were premature, ill, or abandoned. During the 18th and 19th centuries, congenital syphilis was a common cause of infant mortality. The Vaugirard hospital in Paris began to use mercury as a treatment; however, it could not be safely administered to infants. In 1780, it began the process of giving mercury to wet nurses, who could then transmit the treatment in their milk to infected infants.

The practice of wet-nursing was still widespread during World War I, according to the American Red Cross. Working-class women would leave their babies with wet nurses so they could get jobs in factories.

United States

Enslaved Black woman wet-nursing white infant

British colonists brought the practice of wet-nursing with them to North America. Since the arrangement of sending infants away to live with wet nurses was the cause of so many infant deaths, by the 19th century, Americans adopted the practice of having wet nurses live with the employers in order to nurse and care for their charges. This practice had the effect of increasing the death rate for wet nurses' own babies. Many employers would have only kept a wet nurse for a few months at a time since it was believed that the quality of a woman's breast milk would lessen over time.

Since there were no official records kept pertaining to wet nurses or wet-nursed babies, historians lack the knowledge of precisely how many infants were wet-nursed and for how long, whether they lived at home or elsewhere, and how many lived or died. The best source of evidence is found in the "help wanted" ads of newspapers, through complaints about wet nurses in magazines, and through medical journals that acted as employment agencies.

In the Southern United States before the Civil War, it was common practice for enslaved black women to be forced to be wet nurses to their owners' children. In some instances, the enslaved child and the white child would be raised together in their younger years. (Sometimes both babies would be fathered by the same man, the slave-owner; see Children of the plantation.) Visual representations of wet-nursing practices in enslaved communities are most prevalent in representations of the Mammy archetype caricature. Images such as the one in this section represent both a historically accurate practice of enslaved black women wet-nursing their owner's white children, as well as sometimes an exaggerated racist caricaturization of a stereotype of a "Mammy" character.

Egypt

From the mid-1800s to the mid-1900s, and especially after World War I, thousands of Slovene peasant women migrated via Trieste to the cosmopolitan port city of Alexandria. There, these aleksandrinke [sl] undertook various sorts of domestic work for elite Levantine households—"the highly mobile upper strata of Ottoman millets, Jewish, Maronites, Melkite active in international commerce". Enough served as wet nurses that this occupation became almost synonymous with Slovene domestic workers, which resulted in some stigma back home. Married women could leave Alexandria and return to their home village, where they would conceive and bear a child and leave the infant to the care of relatives or a hired wet nurse, while they returned to Egypt to seek new employment and a new charge to nurse.

This constitutes the origin of the archetype of the aleksandrinka as a wet nurse, which came to overpower any other representation of the aleksandrinstvo, despite the fact that empirical evidence demonstrates that only a tiny fraction of alekandrinke at any time worked as wet nurses. The majority of aleksandrinke were working as nannies or chamber maids, they were not breastfeeding the children they were taking care of. The emphasis on lactaction, which marks the hypersexualization of the aleksandrinstvo, was part of the rhetorical stigma surrounding this phenomenon in Slovenia.

Relationships

"Visite Chez la Nourrice" ("Visit to the Wet nurse") by Victor Adam

An infant who has been living with a wet nurse being taken away from its foster parents by its natural mother. By Étienne Aubry

Sometimes, the infant was placed in the home of the wet nurse for several months, as was the case for Jane Austen and her siblings. The Papyrus Oxyrhynchus 91, a receipt from AD 187, attests to the ancient nature of this practice. Sometimes, the wet nurse came to live with the infant's family, filling a position between the monthly nurse (for the immediate post-partum period) and the nanny.

In some cultures, the wet nurse was simply hired as any other employee. In others, however, she had a special relationship with the family, which could incur kinship rights. In Vietnamese family structure, for example, the wet nurse is known as Nhũ mẫu, mẫu meaning "mother". Islam has a highly codified system of milk kinship known as rada. George III of the United Kingdom, born two months premature, had a wet nurse whom he so valued all his life, that her daughter was appointed laundress to the Royal Household, "a sinecure place of great emolument".

Mothers who nurse each other's babies are engaging in a reciprocal act known as cross-nursing or co-nursing.

Current attitudes in Western countries

In contemporary affluent Western societies such as the United States, the act of nursing a baby other than one's own often provokes cultural discomfort. When a mother is unable to nurse her own infant, an acceptable mediated substitute is expressed milk (or especially colostrum), which is donated to milk banks, analogous to blood banks, and processed there by being screened, pasteurized, and usually frozen. Infant formula is also widely available, which its makers claim can be a reliable source of infant nutrition when prepared properly. Dr. Rhonda Shaw notes that Western objections to wet nurses are cultural:

The exchange of body fluids between different women and children, and the exposure of intimate bodily parts make some people uncomfortable. The hidden subtext of these debates has to do with perceptions of moral decency. Cultures with breast fetishes tend to conflate the sexual and erotic breast with the functional and lactating breast.

For some Americans, the subject of wet-nursing is becoming increasingly open for discussion. During a UNICEF goodwill tour to Sierra Leone in 2008, American Mexican actress Salma Hayek decided to breastfeed a local infant in front of the accompanying film crew. The sick one-week-old baby had been born the same day but a year later than Hayek's daughter, who had not yet been weaned. The actress later discussed on camera an anecdote of her Mexican great-grandmother spontaneously breastfeeding a hungry baby in a village.

Current situation elsewhere

Wet nurses are still common in many developing countries, although the practice poses a risk of infections, such as HIV. In China, Indonesia, and the Philippines, a wet nurse may be employed in addition to a nanny as a mark of aristocracy, wealth, and high status. Following the 2008 Chinese milk scandal, in which contaminated infant formula poisoned thousands of babies, the salaries of wet nurses there increased dramatically.

Notable wet nurses

Royal wet nurses are more likely than most to reach the historical record.

In Ancient Egypt, Maia was the wet nurse of King Tutankhamun. Sitre In, the nurse of Hatshepsut, was not a member of the royal family but received the honour of a burial in the royal necropolis in the Valley of the Kings, in tomb KV60. Her coffin has the inscription wr šdt nfrw nswt In, meaning Great Royal Wet Nurse In.

In Asia, Lady Kasuga was the wet nurse of the third Tokugawa shōgun, Iemitsu. Lu Lingxuan was a lady in waiting who served as wet nurse to the emperor Gao Wei. She became exceedingly powerful during his reign and was often criticized by historians for her corruption and treachery. Chinese emperors honoured the Nurse empress dowager. Wet nurses were also common during the Mughal period, with almost every Mughal prince having one. Some prominent ones are Maham Anga for Akbar and Dai Anga for Shah Jahan. Shin Myo Myat was the mother of King Bayinnaung of the Toungoo Dynasty of Burma (Myanmar), and the wet nurse of King Tabinshwehti. The last Emperor of China, Puyi, described Mrs. Wang Chiao as being the only person who was able to control him: "from my infancy until the time I grew up, only my wet nurse, because of her simple language, was able to make me grasp the idea that I was like other people."

In Europe, Hodierna of St Albans was the mother of Alexander Neckam and wet nurse of Richard I of England, and Mrs. Pack was a wet nurse to William, Duke of Gloucester (1689–1700). Geneviève Poitrine was a wet nurse of the Dauphin of France, Louis Joseph, son of King Louis XVI of France and Queen Marie Antoinette. Poitrine was accused of transmitting tuberculosis to the Dauphin and triggering his infant death when aged seven, although since very few pre-adolescent children die from TB, this accusation may have been the result of a misdiagnosis.

Some non-royal wet nurses have also been written about. Halimah bint Abi Dhuayb was the foster mother and wet nurse of the Islamic prophet Muhammad. Petronella Muns was, with her employer, the first Western woman to visit Japan. Naomi Baumslag, author of Milk, Money and Madness, described the legendary capacity of Judith Waterford: "In 1831, on her 81st birthday, she could still produce breast milk. In her prime she unfailingly produced two quarts (four pints or 1.9 litres) of breast milk a day."

Protein phosphorylation

From Wikipedia, the free encyclopedia

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

Model of a phosphorylated serine residue

Serine in an amino acid chain, before and after phosphorylation.

Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural conformation of a protein, causing it to become either activated or deactivated, or otherwise modifying its function. Approximately 13000 human proteins have sites that are phosphorylated.

The reverse reaction of phosphorylation is called dephosphorylation, and is catalyzed by protein phosphatases. Protein kinases and phosphatases work independently and in a balance to regulate the function of proteins.

The amino acids most commonly phosphorylated are serine, threonine, tyrosine in eukaryotes, and also histidine in prokaryotes and plants (though it is now known to be common in humans). These phosphorylations play important and well-characterized roles in signaling pathways and metabolism. However, other amino acids can also be phosphorylated post-translationally, including arginine, lysine, aspartic acid, glutamic acid and cysteine, and these phosphorylated amino acids have recently been identified to be present in human cell extracts and fixed human cells using a combination of antibody-based analysis (for pHis) and mass spectrometry (for all other amino acids).

Protein phosphorylation was first reported in 1906 by Phoebus Levene at the Rockefeller Institute for Medical Research with the discovery of phosphorylated vitellin. However, it was nearly 50 years until the enzymatic phosphorylation of proteins by protein kinases was discovered.

History

In 1906, Phoebus Levene at the Rockefeller Institute for Medical Research identified phosphate in the protein vitellin (phosvitin), and by 1933 had detected phosphoserine in casein, with Fritz Lipmann. However, it took another 20 years before Eugene P. Kennedy described the first ‘enzymatic phosphorylation of proteins’. The first phosphorylase enzyme was discovered by Carl and Gerty Cori in the late 1930s. Carl and Gerty Cori found two forms of glycogen phosphorylase which they named A and B but did not correctly understand the mechanism of the B form to A form conversion. The interconversion of phosphorylase b to phosphorylase a was later described by Edmond Fischer and Edwin Krebs, as well as, Wosilait and Sutherland, involving a phosphorylation/dephosphorylation mechanism. It was found that an enzyme, named phosphorylase kinase and Mg-ATP were required to phosphorylate glycogen phosphorylase by assisting in the transfer of the γ-phosphoryl group of ATP to a serine residue on phosphorylase b. Protein phosphatase 1 is able to catalyze the dephosphorylation of phosphorylated enzymes by removing the phosphate group. Earl Sutherland explained in 1950, that the activity of phosphorylase was increased and thus glycogenolysis stimulated when liver slices were incubated with adrenalin and glucagon. Phosphorylation was considered a specific control mechanism for one metabolic pathway until the 1970s, when Lester Reed discovered that mitochondrial pyruvate dehydrogenase complex was inactivated by phosphorylation. Also in the 1970s, the term multisite phosphorylation was coined in response to the discovery of proteins that are phosphorylated on two or more residues by two or more kinases. In 1975, it was shown that cAMP-dependent proteins kinases phosphorylate serine residues on specific amino acid sequence motifs. Ray Erikson discovered that v-Src was a kinase and Tony Hunter found that v-Src phosphorylated tyrosine residues on proteins in the 1970s. In the early 1980, the amino-acid sequence of the first protein kinase was determined which helped geneticists understand the functions of regulatory genes. In the late 1980s and early 1990s, the first protein tyrosine phosphatase (PTP1B) was purified and the discovery, as well as, cloning of JAK kinases was accomplished which led to many in the scientific community to name the 1990s as the decade of protein kinase cascades. Edmond Fischer and Edwin Krebs were awarded the Nobel prize in 1992 “for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism”.

Abundance

Reversible phosphorylation of proteins is abundant in both prokaryotic and even more so in eukaryotic organisms. For instance, in bacteria 5-10% of all proteins are thought to be phosphorylated. By contrast, it is estimated that one third of all human proteins is phosphorylated at any point in time, with 230,000, 156,000, and 40,000 unique phosphorylation sites existing in human, mouse, and yeast, respectively. In yeast, about 120 kinases (out of ~6000 proteins total) cause 8814 known regulated phosphorylation events, generating about 3,600 phosphoproteins (about 60% of all yeast proteins). Hence, phosphorylation is a universal regulatory mechanism that affects a large portion of proteins. Even if a protein is not phosphorylated itself, its interactions with other proteins may be regulated by phosphorylation of these interacting proteins.

Mechanisms and functions of phosphorylation

Phosphorylation introduces a charged and hydrophilic group in the side chain of amino acids, possibly changing a protein's structure by altering interactions with nearby amino acids. Some proteins such as p53 contain multiple phosphorylation sites, facilitating complex, multi-level regulation. Because of the ease with which proteins can be phosphorylated and dephosphorylated, this type of modification is a flexible mechanism for cells to respond to external signals and environmental conditions.

Kinases phosphorylate proteins and phosphatases dephosphorylate proteins. Many enzymes and receptors are switched "on" or "off" by phosphorylation and dephosphorylation. Reversible phosphorylation results in a conformational change in the structure in many enzymes and receptors, causing them to become activated or deactivated. Phosphorylation usually occurs on serine, threonine, tyrosine and histidine residues in eukaryotic proteins. Histidine phosphorylation of eukaryotic proteins appears to be much more frequent than tyrosine phosphorylation. In prokaryotic proteins phosphorylation occurs on the serine, threonine, tyrosine, histidine or arginine or lysine residues. The addition of a phosphate (PO₄^3-) molecule to a non-polar R group of an amino acid residue can turn a hydrophobic portion of a protein into a polar and extremely hydrophilic portion of a molecule. In this way protein dynamics can induce a conformational change in the structure of the protein via long-range allostery with other hydrophobic and hydrophilic residues in the protein.

One such example of the regulatory role that phosphorylation plays is the p53 tumor suppressor protein. The p53 protein is heavily regulated and contains more than 18 different phosphorylation sites. Activation of p53 can lead to cell cycle arrest, which can be reversed under some circumstances, or apoptotic cell death. This activity occurs only in situations wherein the cell is damaged or physiology is disturbed in normal healthy individuals.

Upon the deactivating signal, the protein becomes dephosphorylated again and stops working. This is the mechanism in many forms of signal transduction, for example the way in which incoming light is processed in the light-sensitive cells of the retina.

Regulatory roles of phosphorylation include:

• Biological thermodynamics of energy-requiring reactions
  • Phosphorylation of Na⁺/K⁺-ATPase during the transport of sodium (Na⁺) and potassium (K⁺) ions across the cell membrane in osmoregulation to maintain homeostasis of the body's water content.
• Mediates enzyme inhibition
  • Phosphorylation of the enzyme GSK-3 by AKT (Protein kinase B) as part of the insulin signaling pathway.
  • Phosphorylation of src tyrosine kinase (pronounced "sarc") by C-terminal Src kinase (Csk) induces a conformational change in the enzyme, resulting in a fold in the structure, which masks its kinase domain, and is thus shut "off".

Membrane transport

Further information: Membrane transport

• Phosphorylation of Na⁺/K⁺-ATPase during the transport of sodium (Na⁺) and potassium (K⁺) ions across the cell membrane in osmoregulation to maintain homeostasis of the body's water content.
• ATP-binding cassette transporter

Protein degradation

• Arginine phosphorylation by McsB kinase marks proteins for degradation by a Clp protease. The arginine phosphorylation system, which is widely distributed across Gram-positive bacteria, appears to be functionally analogous to the eukaryotic ubiquitin–proteasome system.

Enzyme regulation (activation and inhibition)

• The first example of protein regulation by phosphorylation to be discovered was glycogen phosphorylase. Eddie Fisher and Ed Krebs described how phosphorylation of glycogen phosphorylase b converted it to the active glycogen phosphorylase a. It was soon discovered that glycogen synthase, another metabolic enzyme, is inactivated by phosphorylation.
• Phosphorylation of the enzyme GSK-3 by AKT (Protein kinase B) as part of the insulin signaling pathway.
• Phosphorylation of Src tyrosine kinase (pronounced "sarc") by Csk (C-terminal Src kinase) inactivates Src by inducing a conformational change which masks its kinase domain.
• Phosphorylation of the H2AX histones on serine 139, within two million bases (0.03% of the chromatin) surrounding a double-strand break in DNA, is needed for repair of the double-strand break. Phosphorylation of methylpurine DNA glycosylase at serine 172 is required for base excision repair of alkylated base damage.

Protein-protein interactions

• Phosphorylation of the cytosolic components of NADPH oxidase, a large membrane-bound, multi-protein enzyme present in phagocytic cells, plays an important role in the regulation of protein-protein interactions in the enzyme.
• Important in protein degradation.
  • In the late 1990s, it was recognized that phosphorylation of some proteins causes them to be degraded by the ATP-dependent ubiquitin/proteasome pathway. These target proteins become substrates for particular E3 ubiquitin ligases only when they are phosphorylated.

Signaling networks

Elucidating complex signaling pathway phosphorylation events can be difficult. In cellular signaling pathways, protein A phosphorylates protein B, and B phosphorylates C. However, in another signaling pathway, protein D phosphorylates A, or phosphorylates protein C. Global approaches such as phosphoproteomics, the study of phosphorylated proteins, which is a sub-branch of proteomics, combined with mass spectrometry-based proteomics, have been utilised to identify and quantify dynamic changes in phosphorylated proteins over time. These techniques are becoming increasingly important for the systematic analysis of complex phosphorylation networks. They have been successfully used to identify dynamic changes in the phosphorylation status of more than 6000 sites after stimulation with epidermal growth factor. Another approach for understanding Phosphorylation Network, is by measuring the genetic interactions between multiple phosphorylating proteins and their targets. This reveals interesting recurring patterns of interactions – network motifs. Computational methods have been developed to model phosphorylation networks and predict their responses under different perturbations.

Phosphorylation of histones

Eukaryotic DNA is organized with histone proteins in specific complexes called chromatin. The chromatin structure functions and facilitates the packaging, organization and distribution of eukaryotic DNA. However, it has a negative impact on several fundamental biological processes such as transcription, replication and DNA repair by restricting the accessibility of certain enzymes and proteins. Post-translational modification of histones such as histone phosphorylation has been shown to modify the chromatin structure by changing protein:DNA or protein:protein interactions. Histone post-translational modifications modify the chromatin structure. The most commonly associated histone phosphorylation occurs during cellular responses to DNA damage, when phosphorylated histone H2A separates large chromatin domains around the site of DNA breakage. Researchers investigated whether modifications of histones directly impact RNA polymerase II directed transcription. Researchers choose proteins that are known to modify histones to test their effects on transcription, and found that the stress-induced kinase, MSK1, inhibits RNA synthesis. Inhibition of transcription by MSK1 was most sensitive when the template was in chromatin, since DNA templates not in chromatin were resistant to the effects of MSK1. It was shown that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1. Thus results suggested that the acetylation of histones can stimulate transcription by suppressing an inhibitory phosphorylation by a kinase as MSK1.

Kinases

Further information: Kinase

Within a protein, phosphorylation can occur on several amino acids. Phosphorylation on serine is thought to be the most common, followed by threonine. Tyrosine phosphorylation is relatively rare but lies at the head of many protein phosphorylation signalling pathways (e.g. in tyrosine kinase-linked receptors) in most of the eukaryotes. Phosphorylation on amino acids, such as serine, threonine, and tyrosine results in the formation of a phosphoprotein, when the phosphate group of the phosphoprotein reacts with the -OH group of a Ser, Thr, or Tyr sidechain in an esterification reaction. However, since tyrosine phosphorylated proteins are relatively easy to purify using antibodies, tyrosine phosphorylation sites are relatively well understood. Histidine and aspartate phosphorylation occurs in prokaryotes as part of two-component signaling and in some cases in eukaryotes in some signal transduction pathways. The analysis of phosphorylated histidine using standard biochemical and mass spectrometric approaches is much more challenging than that of Ser, Thr or Tyr. In prokaryotes, archea, and some lower eukaryotes histidine's nitrogen act as a nucleophile and binds to a phosphate group. Once histidine is phosphorylated the regulatory domain of the response regulator catalyzes the transfer of the phosphate to aspartate.

Receptor tyrosine kinases

The AXL receptor tyrosine kinase, showing the symmetry of the dimerized receptors

While tyrosine phosphorylation is found in relatively low abundance, it is well studied due to the ease of purification of phosphotyrosine using antibodies. Receptor tyrosine kinases are an important family of cell surface receptors involved in the transduction of extracellular signals such as hormones, growth factors, and cytokines. Binding of a ligand to a monomeric receptor tyrosine kinase stabilizes interactions between two monomers to form a dimer, after which the two bound receptors phosphorylate tyrosine residues in trans. Phosphorylation and activation of the receptor activates a signaling pathway through enzymatic activity and interactions with adaptor proteins. Signaling through the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is critical for the development of multiple organ systems including the skin, lung, heart, and brain. Excessive signaling through the EGFR pathway is found in many human cancers.

Cyclin-dependent kinases

Cyclin-dependent kinases (CDKs) are serine-threonine kinases which regulate progression through the eukaryotic cell cycle. CDKs are catalytically active only when bound to a regulatory cyclin. Animal cells contain at least nine distinct CDKs which bind to various cyclins with considerable specificity. CDK inhibitors (CKIs) block kinase activity in the cyclin-CDK complex to halt the cell cycle in G1 or in response to environmental signals or DNA damage. The activity of different CDKs activate cell signaling pathways and transcription factors that regulate key events in mitosis such as the G1/S phase transition. Earlier cyclin-CDK complexes provide the signal to activate subsequent cyclin-CDK complexes.

Sites

There are thousands of distinct phosphorylation sites in a given cell since:

1. There are thousands of different kinds of proteins in any particular cell (such as a lymphocyte).
2. It is estimated that 1/10 to 1/2 of proteins are phosphorylated (in some cellular state).
3. Independent studies indicate that 30-65% of proteins in the human genome and ~50% of proteins in the yeast genome may be phosphorylated.
4. A statistical analysis of numerous high-throughput and low-throughput experiments estimates that 230,000 156,000 and 40,000 phosphorylation sites exist in human, mouse and yeast, respectively
5. Phosphorylation often occurs on multiple distinct sites on a given protein.

Since phosphorylation of any site on a given protein can change the function or localization of that protein, understanding the "state" of a cell requires knowing the phosphorylation state of its proteins. For example, if amino acid Serine-473 ("S473") in the protein AKT is phosphorylated, AKT is, in general, functionally active as a kinase. If not, it is an inactive kinase.

Phosphorylation sites are crucial for proteins and their transportation and functions. They are the covalent modification of proteins through reversible phosphorylation. This enables proteins to stay inbound within a cell since the negative phosphorylated site disallows their permeability through the cellular membrane. Protein dephosphorylation allows the cell to replenish phosphates through release of pyrophosphates which saves ATP use in the cell. An example of phosphorylating enzyme is found in E. coli bacteria. It possesses alkaline phosphatase in its periplasmic region of its membrane. The outermost membrane is permeable to phosphorylated molecules however the inner cytoplasmic membrane is impermeable due to large negative charges. In this way, the E. coli bacteria stores proteins and pyrophosphates in its periplasmic membrane until either are needed within the cell.

Recent advancement in phosphoproteomic identification has resulted in the discoveries of countless phosphorylation sites in proteins. This required an integrative medium for accessible data in which known phosphorylation sites of proteins are organized. A curated database of dbPAF was created, containing known phosphorylation sites in H. sapiens, M. musculus, R. norvegicus, D. melanogaster, C. elegans, S. pombe and S. cerevisiae. The database currently holds 294,370 non-redundant phosphorylation sites of 40,432 proteins. Other tools of phosphorylation prediction in proteins include NetPhos for eukaryotes, NetPhosBac for bacteria and ViralPhos for viruses.

Serine/Threonine

There are a large variety of serine residues, and the phosphorylation of each residue can lead to different metabolic consequences.

• Protein kinase N1 is responsible for the phosphorylation of the TNF receptor-associated factor (TRAF1) on serine 139 under specific conditions. Murine TRAF1 is also phosphorylated by the same kinase, which leads to the silencing of IKK/NF-κB activity. The elimination of phosphorylation on serine 139 can be achieved by the replacement of TRAF1 with an Alanine residue, which consequently leads to the improved recruitment of TBK1.
• At the serine 789 residue, FGFR1 is phosphorylated by RSK2 when the kinase is in its active form. The signaling capabilities of FGFR1 at the serine 777 site can be weakened by phosphorylation. Serine 1047 and serine 1048 have been linked to the decreased binding affinity of ubiquitin ligase c-Cbl to EFGR when they are phosphorylated.
• When serine 349 is phosphorylated, the binding affinity between protein complex p62 and the protein Keap1 is strengthened, which is linked to stress response.
• When serine 337 is phosphorylated by protein kinase A in vitro, the DNA binding efficiency of the p50 subunit of NF-κB is greatly increased.

Phosphorylation of serine and threonine residues is known to crosstalk with O-GlcNAc modification of serine and threonine residues.

Tyrosine

Main article: Tyrosine phosphorylation

Tyrosine phosphorylation is fast to react and the reaction can be reversed. Being one of the major regulatory mechanisms in signal transduction - cell growth, differentiation, migration and metabolic homeostasis are cellular processes maintained by tyrosine phosphorylation. The function of protein tyrosine kinases and protein-tyrosine phosphatase counterbalances the level of phosphotyrosine on any protein. The malfunctioning of specific chains of protein tyrosine kinases and protein tyrosine phosphatase has been linked to multiple human diseases such as obesity, insulin resistance, and type 2 diabetes mellitus. Phosphorylation on tyrosine doesn't occur in just eukaryotes but has been discovered to occur in a selection of bacterial species and present among prokaryotes. Phosphorylation on tyrosine maintains the cellular regulation in bacteria similar to its function in eukaryotes.

Arginine

Arginine phosphorylation in many Gram-positive bacteria marks proteins for degradation by a Clp protease.

Non-canonical phosphorylation on His, Asp, Cys, Glu, Arg and Lys in human cells

Recent studies from Claire E Eyers lab confirm widespread human protein phosphorylation on multiple non-canonical amino acids, including motifs containing phosphorylated histidine (1 and 3 positions), aspartate, cysteine, glutamate, arginine and lysine in HeLa cell extracts. Due to the chemical and thermal lability of these phosphorylated residues, special procedures and separation techniques are required for preservation alongside the heat stable 'classical' Ser, Thr and Tyr phosphorylation.

Detection and characterization

Antibodies can be used as powerful tool to detect whether a protein is phosphorylated at a particular site. Antibodies bind to and detect phosphorylation-induced conformational changes in the protein. Such antibodies are called phospho-specific antibodies; hundreds of such antibodies are now available. They are becoming critical reagents both for basic research and for clinical diagnosis.

Example of posttranslational modification detected on a 2D gel (spot boundaries delimited by analysis software, identification by mass spectrometry, P46462 is the protein ID in Expasy)

Posttranslational modification (PTM) isoforms are easily detected on 2D gels. Indeed, phosphorylation replaces neutral hydroxyl groups on serines, threonines, or tyrosines with negatively charged phosphates with pKs near 1.2 and 6.5. Thus, below pH 5.5, phosphates add a single negative charge; near pH 6.5, they add 1.5 negative charges; above pH 7.5, they add 2 negative charges. The relative amount of each isoform can also easily and rapidly be determined from staining intensity on 2D gels.

In some very specific cases, the detection of the phosphorylation as a shift in the protein's electrophoretic mobility is possible on simple 1-dimensional SDS-PAGE gels, as it's described for instance for a transcriptional coactivator by Kovacs et al. Strong phosphorylation-related conformational changes (that persist in detergent-containing solutions) are thought to underlie this phenomenon. Most of the phosphorylation sites for which such a mobility shift has been described fall in the category of SP and TP sites (i.e. a proline residue follows the phosphorylated serine or threonine residue).

More recently large-scale mass spectrometry analyses have been used to determine sites of protein phosphorylation. Over the last 4 years, dozens of studies have been published, each identifying thousands of sites, many of which were previously undescribed. Mass spectrometry is ideally suited for such analyses using HCD or ETD fragmentation, as the addition of phosphorylation results in an increase in the mass of the protein and the phosphorylated residue. Advanced, highly accurate mass spectrometers are needed for these studies, limiting the technology to labs with high-end mass spectrometers. However, the analysis of phosphorylated peptides by mass spectrometry is still not as straightforward as for “regular”, unmodified peptides. Recently EThcD has been developed combining electron-transfer and higher-energy collision dissociation. Compared to the usual fragmentation methods, EThcD scheme provides more informative MS/MS spectra for unambiguous phosphosite localization.

A detailed characterization of the sites of phosphorylation is very difficult, and the quantitation of protein phosphorylation by mass spectrometry requires isotopic internal standard approaches. A relative quantitation can be obtained with a variety of differential isotope labeling technologies. There are also several quantitative protein phosphorylation methods, including fluorescence immunoassays, Microscale thermophoresis, FRET, TRF, fluorescence polarization, fluorescence-quenching, mobility shift, bead-based detection, and cell-based formats.

Evolution

Protein phosphorylation is common among all clades of life, including all animals, plants, fungi, bacteria, and archaea. The origins of protein phosphorylation mechanisms are ancestral and have diverged greatly between different species. In eukaryotes, it is estimated that between 30 - 65% of all proteins may be phosphorylated, with tens or even hundreds of thousands of distinct phosphorylation sites. Some phosphorylation sites appear to have evolved as conditional "off" switches, blocking the active site of an enzyme, such as in the prokaryotic metabolic enzyme isocitrate dehydrogenase. However, in the case of proteins that must be phosphorylated to be active, it is less clear how they could have emerged from non-phosphorylated ancestors. It has been shown that a subset of serine phosphosites are often replaced by acidic residues such as aspartate and glutamate between different species. These anionic residues can interact with cationic residues such as lysine and arginine to form salt bridges, stable non-covalent interactions that alter a protein's structure. These phosphosites often participate in salt bridges, suggesting that some phosphorylation sites evolved as conditional "on" switches for salt bridges, allowing these proteins to adopt an active conformation only in response to a specific signal.

There are ~600 known eukaryotic protein kinases, making them one of the largest gene families. Most phosphorylation is carried out by a single superfamily of protein kinases that share a conserved kinase domain. Protein phosphorylation is highly conserved in pathways central to cell survival, such as cell cycle progression relying on Cyclin-dependent kinases (CDKs), but individual phosphorylation sites are often flexible. Targets of CDK phosphorylation often have phosphosites in disordered segments, which are found in non-identical locations even in close species. Conversely, targets of CDK phosphorylation in structurally defined regions are more highly conserved. While CDK activity is critical for cell growth and survival in all eukaryotes, only very few phosphosites show strong conservation of their precise positions. Positioning is likely to be highly important for phosphates that allosterically regulate protein structure, but much more flexible for phosphates that interact with phosphopeptide-binding domains to recruit regulatory proteins.

Comparisons between eukaryotes and prokaryotes

Protein phosphorylation is a reversible post-translational modification of proteins. In eukaryotes, protein phosphorylation functions in cell signaling, gene expression, and differentiation. It is also involved in DNA replication during the cell cycle, and the mechanisms that cope with stress-induced replication blocks. Compared to eukaryotes, prokaryotes use Hanks-type kinases and phosphatases for signal transduction. Whether or not the phosphorylation of proteins in bacteria can also regulate processes like DNA repair or replication still remains unclear.

Compared to the protein phosphorylation of prokaryotes, studies of protein phosphorylation in eukaryotes from yeast to human cells have been rather extensive. It is known that eukaryotes rely on the phosphorylation of the hydroxyl group on the side chains of serine, threonine, and tyrosine for cell signaling. These are the main regulatory post-translational modifications in eukaryotic cells but the protein phosphorylation of prokaryotes are less intensely studied. While serine, threonine, and tyrosine are phosphorylated in eukaryotes, histidine and aspartate is phosphorylated in prokaryotes, plants and non-plant eukaryotes. In bacteria, histidine phosphorylation occurs in the phosphoenolpyruvate-dependent phosphotransferase systems (PTSs), which are involved in the process of internalization as well as the phosphorylation of sugars.

Protein phosphorylation by protein kinase was first shown in E. coli and Salmonella typhimurium but has since been demonstrated in many other bacterial cells. It was found that bacteria use histidine and aspartate phosphorylation as a model for bacterial signaling transduction but in the last few years there has been evidence that has shown that serine, threonine, and tyrosine phosphorylation are also present in bacteria. It was shown that bacteria carry kinases and phosphatases similar to that of their eukaryotic equivalent but they have also developed unique kinases and phosphatases not found in eukaryotes.

Pathology

Abnormal protein phosphorylation has been implicated in a number of diseases, notably cancer, but also Alzheimer's disease, Parkinson's disease, and other degenerative disorders.

Tau protein belongs to a group of Microtubule Associated Proteins (MAPs) which, among several things, help stabilize microtubules in cells, including neurons. Association and stabilizing activity of tau protein depends on its phosphorylated state. In Alzheimer's disease, due to misfoldings and abnormal conformational changes in tau protein structure, it is rendered ineffective at binding to microtubules and thus unable to keep the neural cytoskeletal structure organized during neural processes; in fact abnormal tau inhibits and disrupts microtubule organization and disengages normal tau from microtubules into cytosolic phase. The misfoldings lead to the abnormal aggregation into fibrillary tangles inside the neurons, the hallmark of Alzheimer's disease. There is an adequate amount that the tau protein needs to be phosphorylated to function, but hyperphosphorylation of tau protein is thought to be one of the major influences on its incapacity to associate. Phosphatases PP1, PP2A, PP2B, and PP2C dephosphorylate tau protein in vitro, and their activities have found to be reduced in areas of the brain in Alzheimer patients. Tau phosphoprotein is three to fourfold hyperphosphorylated in an Alzheimer patient compared to an aged non-afflicted individual. Alzheimer disease tau seems to remove MAP1 and MAP2 (two other major associated proteins) from microtubules and this deleterious effect is reversed when dephosphorylation is performed, evidencing hyperphosphorylation as the sole cause of the crippling activity.

Parkinson's disease

α-Synuclein is a protein that is associated with Parkinson's disease. This protein, in humans, is encoded by the SNCA gene, and in its native form, α-Synuclein is involved in the recycling of the synaptic vesicles that carry neurotransmitters and naturally occurs in an unfolded form. Elevated levels of α-Synuclein are found in patients with Parkinson's disease, and there seems to be a positive correlation between the amount of the α-Synuclein protein present in the patient and the severity of the disease.

Phosphorylation of the amino acid Ser¹²⁹ in the α-Synuclein protein has a profound effect on the severity of the disease. There seem to be correlation between the total α-Synuclein concentration (unphosphorylated) and the severity of the symptoms in Parkinson's disease patients. Healthy patients seem to have higher levels of unphosphorylated α-Synuclein than patients with Parkinson's disease. Moreover, the measurement of the changes in the ratio of concentrations of phosphorylated α-Synuclein to unphosphorylated α-Synuclein within a patient could be a potential marker of the disease progression. Antibodies that target α-Synuclein at phosphorylated Serine129 are widely used to study the molecular aspects of synucleinopathies 

Phosphorylation of Ser¹²⁹ is associated with the aggregation of the protein and further damage to the nervous system. Furthermore, the aggregation of phosphorylated α-Synuclein can be enhanced if a presynaptic scaffold protein Sept4 is present in insufficient quantities. It is important to note that direct interaction of α-Synuclein with Sept4 protein inhibits the phosphorylation of Ser¹²⁹. Note however that phosphorylation of Ser¹²⁹ can be observed without synuclein aggregation in conditions of overexpression.

Holistic education

From Wikipedia, the free encyclopedia

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

Holistic education is a movement in education that seeks to engage all aspects of the learner, including mind, body, and spirit. Its philosophy, which is also identified as holistic learning theory, is based on the premise that each person finds identity, meaning, and purpose in life through connections to their local community, to the natural world, and to humanitarian values such as compassion and peace.

Holistic education aims to call forth from people an intrinsic reverence for life and a passionate love of learning, gives attention to experiential learning, and places significance on "relationships and primary human values within the learning environment". The term "holistic education" is most often used to refer to the more democratic and humanistic types of alternative education.

Background

Jan Christiaan Smuts in 1947

Title Page of the 1926 book ":Holism and Evolution" by Jan Christiaan Smuts

Holistic education's origins has been associated with the emergence of the concept of instruction in ancient Greece and other indigenous cultures. This involved the method that focused on the whole person instead of one or some segments of an individual's experience. It formed part of the view that the world is a single whole and that learning cannot be separated from all of man's experiences.

The term holistic education has been attributed to the South African military leader, statesman, scholar and philosopher, Field Marshal General Jan Christiaan Smuts (1870-1950), who is noted for his role in the foundation of the League of Nations, and the formation of the international peace organization, the United Nations. He drew from the ancient Greek conceptualization of holistic education to propose a modern philosophy of learning.

Smuts is considered the founder of "Holism", which he derived from the Greek word ολος, which means "whole". In his 1926 book Holism and Evolution, Smuts describes "holism" as the tendency in nature to form wholes that are greater than the sum of the parts through creative evolution. Today, this work is recognized as the foundation theory for systems thinking, complexity theory, neural networks, semantic holism, holistic education, and the general systems theory in ecology. Smuts' "holism" was also the inspiration for Emile Durkheim's concept of the "holistic society", as well as Alfred Adler's psychological approach, which views the individual as an "integrated whole".

There are also sources that credit Rudolph Steiner, John Dewey, and Maria Montessori as the originator of the modern model of holistic education. Steiner, particularly, developed a holistic education framework based on the works of Johann Wolfgang von Goethe and H.P. Blavatsky. It introduced the concept of "imaginative teaching" and its role in the learner's self-actualization.

Development

It is difficult to map the history of holistic education, as in some respects its core ideas are not new but "timeless and found in the sense of wholeness in humanity's religious impetus".

The explicit application of holistic ideas to education has a clear tradition, however, whose originating theorists include: Jean-Jacques Rousseau, Ralph Waldo Emerson, Henry Thoreau, Bronson Alcott, Johann Pestalozzi, and Friedrich Fröbel.

More recent theorists are Rudolf Steiner, Maria Montessori, Francis Parker, John Dewey, Francisco Ferrer John Caldwell Holt, George Dennison Kieran Egan, Howard Gardner, Jiddu Krishnamurti, Carl Jung, Abraham Maslow, Carl Rogers, Paul Goodman, Ivan Illich, and Paulo Freire.

Many scholars feel the modern "look and feel" of holistic education coalesced through two factors: the rise of humanist philosophies after World War II and the cultural paradigm shift beginning in the mid-1960s. In the 1970s, after the holism movement in psychology became much more mainstream, "an emerging body of literature in science, philosophy and cultural history provided an overarching concept to describe this way of understanding education – a perspective known as holism."

In July 1979, the first National Holistic Education Conference took place at the University of California at San Diego. The conference was presented by The Mandala Society and The National Center for the Exploration of Human Potential and was titled Mind: Evolution or Revolution? The Emergence of Holistic Education. For six years after, the Holistic Education Conference was combined with the Mandala Holistic Health Conferences at the University of California, San Diego. About three thousand professionals participated each year. Out of these conferences came the annual Journals of Holistic Health. Holistic education became an identifiable area of study and practice in the mid-1980s in North America. Since the early 2000s, some of the historically separate academic areas, Science, Technology, Engineering, and Mathematics (STEM) on the one hand, and the Humanities, Arts, and Social Sciences (HASS) on the other, have found new holistic common ground, as demonstrated in consensus reports on Integrating Social and Behavioral Sciences Within the Weather Enterprise (2018) and The Integration of the Humanities and Arts with Sciences, Engineering, and Medicine in Higher Education. Branches from the Same Tree (2018).

Philosophical framework for holistic education

Holistic education aims at helping students be the most that they can be. Abraham Maslow referred to this as "self-actualization". Education with a holistic perspective is concerned with the development of every person's intellectual, emotional, social, physical, artistic, creative and spiritual potentials. It seeks to engage students in the teaching/learning process and encourages personal and collective responsibility.

In describing the general philosophy of holistic education, Robin Ann Martin and Scott Forbes (2004) divided their discussion into two categories: the idea of "ultimacy" and Basil Bernstein's notion of sagacious competence.

Ultimacy

1. Religious; as in becoming "enlightened". You see the light out of difficulties and challenges. This can be done through increased spirituality. Spirituality is an important component in holistic education as it emphasizes the connectedness of all living things and stresses the "harmony between the inner life and outer life".
2. Psychological; as in Maslow's "self-actualization". Holistic education believes that each person should strive to be all that they can be in life. There are no deficits in learners, just differences.
3. Undefined; as in a person developing to the ultimate extent a human could reach and, thus, moving towards the highest aspirations of the human spirit.

Sagacious competence

1. Freedom (in a psychological sense).
2. Good-judgment (self-governance).
3. Meta learning (each student learns in their "own way").
4. Social ability (more than just learning social skills).
5. Refining Values (development of character).
6. Self Knowledge (emotional development).

Curriculum

An application of holistic education to a curriculum has been described as transformational learning where the instruction recognizes the wholeness of the learner and that he and the curriculum are not seen as separate but connected. According to John Miller, the position is similar to the Quaker belief that there is "that of God in every one".

Various attempts to articulate the central themes of a holistic education, seeking to educate the whole person, have been made:

• In holistic education the basic three R's have been said to be education for: Relationships, Responsibility and Reverence for all life.

• First, children need to learn about themselves. This involves learning self-respect and self-esteem. Second, children need to learn about relationships. In learning about their relationships with others, there is a focus on social "literacy" (learning to see social influence) and emotional "literacy" (one's own self in relation to others). Third, children need to learn about resilience. This entails overcoming difficulties, facing challenges and learning how to ensure long-term success. Fourth, children need to learn about aesthetics – This encourages the student to see the beauty of what is around them and learn to have awe in life.

• Curriculum is derived from the teacher listening to each child and helping the child bring out what lies within oneself.

Tools/teaching strategies of holistic education

With the goal of educating the whole child, holistic education promotes several strategies to address the question of how to teach and how people learn. First, the idea of holism advocates a transformative approach to learning. Rather than seeing education as a process of transmission and transaction, transformative learning involves a change in the frames of reference that a person might have. This change may include points of view, habits of mind, and worldviews. Holism understands knowledge as something that is constructed by the context in which a person lives. Therefore, teaching students to reflect critically on how we come to know or understand information is essential. As a result, if "we ask students to develop critical and reflective thinking skills and encourage them to care about the world around them they may decide that some degree of personal or social transformation is required."

Second, the idea of connections is emphasized as opposed to the fragmentation that is often seen in mainstream education. This fragmentation may include the dividing of individual subjects, dividing students into grades, etc. Holism sees the various aspects of life and living as integrated and connected, therefore, education should not isolate learning into several different components. Martin (2002) illustrates this point further by stating that, "Many alternative educators argue instead that who the learners are, what they know, how they know it, and how they act in the world are not separate elements, but reflect the interdependencies between our world and ourselves". Included in this idea of connections is the way that the classroom is structured. Holistic school classrooms are often small and consist of mixed-ability and mixed-age students. They are flexible in terms of how they are structured so that if it becomes appropriate for a student to change classes, (s)he is moved regardless of what time of year it is on the school calendar. Flexible pacing is key in allowing students to feel that they are not rushed in learning concepts studied, nor are they held back if they learn concepts quickly.

Third, along the same thread as the idea of connections in holistic education, is the concept of transdisciplinary inquiry. Transdisciplinary inquiry is based on the premise that division between disciplines is eliminated. One must understand the world in wholes as much as possible and not in fragmented parts. "Transdisciplinary approaches involve multiple disciplines and the space between the disciplines with the possibility of new perspectives 'beyond' those disciplines. Where multidisciplinary and interdisciplinary inquiry may focus on the contribution of disciplines to an inquiry transdisciplinary inquiry tends to focus on the inquiry issue itself."

Fourth, holistic education proposes that meaningfulness is also an important factor in the learning process. People learn better when what is being learned is important to them. Holistic schools seek to respect and work with the meaning structures of each person. Therefore, the start of a topic would begin with what a student may know or understand from their worldview, what has meaning to them rather than what others feel should be meaningful to them. Meta-learning is another concept that connects to meaningfulness. In finding inherent meaning in the process of learning and coming to understand how they learn, students are expected to self-regulate their own learning. However, they are not completely expected to do this on their own. Because of the nature of community in holistic education, students learn to monitor their own learning through interdependence on others inside and outside of the classroom.

Finally, as mentioned above, community is an integral aspect in holistic education. As relationships and learning about relationships are keys to understanding ourselves, so the aspect of community is vital in this learning process. Scott Forbes stated, "In holistic education the classroom is often seen as a community, which is within the larger community of the school, which is within the larger community of the village, town, or city, and which is, by extension, within the larger community of humanity."

Teacher's role

In holistic education, the teacher is seen less as person of authority who leads and controls but rather is seen as "a friend, a mentor, a facilitator, or an experienced traveling companion". Schools should be seen as places where students and adults work toward a mutual goal. Open and honest communication is expected and differences between people are respected and appreciated. Cooperation is the norm, rather than competition. Thus, many schools incorporating holistic beliefs do not give grades or rewards. The reward of helping one another and growing together is emphasized rather than being placed above one another.