Melanin

Broadly, melanin is any of the polyacetylene, polyaniline, and polypyrrole "blacks" or their mixed copolymers. The most common form of biological melanin is a polymer of either or both of two monomer molecules: indolequinone, and dihydroxyindole carboxylic acid. In contrast, some fungal melanin is polyacetylene black. Melanin exists in the plant, animal and protista kingdoms, where it serves as a pigment. The presence of melanin in the archaea and bacteria kingdoms is an issue of ongoing debate amongst researchers in the field.

Melanin in humans
In humans, melanin is found in skin, hair, the coat of the retina, the renal medulla and zona reticularis of the adrenal gland, the inner ear, and the substantia nigra (in Latin, literally "black substance") and locus ceruleus ("blue spot") of the brain. Melanin is the primary determinant of human skin color.

Dermal melanin is produced by melanocytes, which are found in the stratum basale of the epidermis. Although human beings generally possess a similar concentration of melanocytes in their skin, the melanocytes in some individuals and races more frequently express the melanin-producing genes, thereby conferring a greater concentration of skin melanin. Some individual animals and humans have no or very little melanin in their bodies, which is a condition known as albinism.

Because melanin is an aggregate of smaller component molecules, there are a number of different types of melanin with differing proportions and bonding patterns of these component molecules. Both pheomelanin and eumelanin are found in human skin and hair, but eumelanin is the most abundant melanin in humans, as well as the form most likely to be deficient in albinism.

Eumelanin polymers have long been thought to comprise numerous cross-linked dihydroxyindole polymers; recent research into the electrical properties of eumelanin, however, has indicated that it may consist of more basic oligomers adhering to one another by some other mechanism. Thus, the precise nature of eumelanin's molecular structure is once again the object of study. Eumelanin is found in hair and skin, and colors hair from brown to black. In humans, it is more abundant in peoples with dark skin.

Pheomelanin is also found in hair and skin and is more abundant in fair-skinned humans. Pheomelanin imparts a yellow to reddish hue and, thus, is found in particularly large quantities in red hair.

Neuromelanin is a byproduct of dopamine metabolism, and is found in the substantia nigra and locus ceruleus of the human brain. Its role, if any, is uncertain. Neuromelanin is not present in the brains of all mammals, but it has been detected in primates and in carnivores such as cats and dogs.

Synthetic pathway

The first step of the synthetic pathway for both eumelanins and pheomelanins is mediated by tyrosinase:
 * Tyrosine &rarr; DOPA &rarr; dopaquinone

Dopaquinone can combine with cysteine by two pathways to benzothiazines and pheomelanins
 * Dopaquinone + cysteine &rarr; 5-S-cysteinyldopa &rarr; benzothiazine intermediate &rarr; pheomelanin


 * Dopaquinone + cysteine &rarr; 2-S-cysteinyldopa &rarr; benzothiazine intermediate &rarr; pheomelanin

Alternatively, dopaquinone can be converted to leucodopachrome and follow two more pathways to the eumelanins
 * Dopaquinone &rarr; leucodopachrome &rarr; dopachrome &rarr; 5,6-dihydroxyindole-2-carboxylic acid &rarr; quinone &rarr; eumelanin


 * Dopaquinone &rarr; leucodopachrome &rarr; dopachrome &rarr; 5,6-dihydroxyindole &rarr; quinone &rarr; eumelanin

Melanin deficiency in genetic disorders and disease states
Melanin deficiency has been connected for some time with various genetic abnormalities and disease states.

There are approximately ten different types of oculocutaneous albinism, which is mostly an autosomal recessive disorder. Certain ethnicities have higher incidences of different forms. For example, the most common type, called oculocutaneous albinism type 2 (OCA2), is especially frequent among people of indigenous African descent. It is an autosomal recessive disorder characterized by a congenital reduction or absence of melanin pigment in the skin, hair and eyes. The estimated frequency of OCA2 among African-Americans is 1 in 10,000, which contrasts with a frequency of 1 in 36,000 in white Americans. In some African nations, the frequency of the disorder is even higher, ranging from 1 in 2,000 to 1 in 5,000. Another form of Albinism, the "yellow oculocutaneous albinism", appears to be more prevalent among the Amish, who are of primarily Swiss and German ancestry. People with this IB variant of the disorder commonly have white hair and skin at birth, but rapidly develop normal skin pigmentation in infancy.

Ocular albinism affects not only eye pigmentation, but visual acuity, as well. People with albinism typically test poorly, within the 20/60 to 20/400 range. Additionally, two forms of albinism, with approximately 1 in 2700 most prevalent among people of Puerto Rican origin, are associated with mortality beyond melanoma-related deaths.

"Mortality also is increased in patients with Hermansky-Pudlak syndrome and Chediak-Higashi syndrome. Patients with Hermansky-Pudlak syndrome have a bleeding diathesis secondary to platelet dysfunction and also experience restrictive lung disease (pulmonary fibrosis), inflammatory bowel disease, cardiomyopathy, and renal disease. Patients with Chediak-Higashi syndrome are susceptible to infection and also can develop lymphofollicular malignancy."

The role that melanin deficiency plays in such disorders remains under study.

The connection between albinism and deafness has been well known, though poorly understood, for more than a century-and-a-half. In his 1859 treatise On the Origin of Species, Charles Darwin observed that "cats which are entirely white and have blue eyes are generally deaf". In humans, hypopigmentation and deafness occur together in the rare Waardenberg's syndrome, predominantly observed among Hopi American Indians. The incidence of albinism in Hopi Indians has been estimated as approximately 1 in 200 individuals. Interestingly, similar patterns of albinism and deafness have been found in other mammals, including dogs and rodents. However, a lack of melanin per se does not appear to be directly responsible for deafness associated with hypopigmentation, as most individuals lacking the enzymes required to synthesize melanin have normal auditory function. Instead the absence of melanocytes in the stria vascularis of the inner ear results in cochlear impairment, though why this is is not fully understood.

Persons with Parkinson's disease, a disorder that affects neuromotor functioning, have been shown to have decreased neuromelanin in the substantia nigra as consequence of diminished dopamine synthesis. While no correlation between race and the level of neuromelanin in the substantia nigra has been observed, the significantly lower incidence of Parkinson's in blacks than in whites has "prompt[ed] some to suggest that cutaneous melanin might somehow serve to protect the neuromelanin in substantia nigra from external toxins."

In addition to melanin deficiency, the molecular weight of the melanin polymer may be decreased due to various factors such as oxidative stress, exposure to light, perturbation in its association with melanosomal matrix proteins, changes in pH or in local concentrations of metal ions. A decreased molecular weight or a decrease in the degree of polymerization of ocular melanin has been proposed to turn the normally anti-oxidant polymer into a pro-oxidant. In its pro-oxidant state, melanin has been suggested to be involved in the causation and progression of macular degeneration and melanoma. (Ref: Pigment cell Res. 2001; volume 14: pages 148-154. "Redox regulation in human melanocytes and melanoma")

Melanin and human adaptation
Melanocytes insert granules of melanin into specialized cellular vesicles called melanosomes. These are then transferred into the other skin cells of the human epidermis. The melanosomes in each recipient cell accumulate atop the cell nucleus, where they protect the nuclear DNA from mutations caused by the ionizing radiation of the sun's ultraviolet rays. People whose ancestors lived for long periods in the regions of the globe near the equator generally have larger quantities of eumelanin in their skins. This makes their skins brown or black and protects them against high levels of exposure to the sun, which more frequently results in melanomas in fairer-skinned people. Darker skin also tends to remain more supple and shows fewer lines and wrinkles over time than fairer skin. As a result, the faces of dark skinned people generally tend to look more youthful longer than light skinned people.

With humans, exposure to sunlight stimulates the liver to produce vitamin D. Because high levels of cutaneous melanin act as a natural sun screen, dark skin can be a risk factor for vitamin D deficiency.

"In Scotland, which lies at a northern latitude, descendants of the Britons have white skin. When their skin is exposed to the meager sunlight, the scant amount of melanin their skin produces is unable to block the sunlight. Therefore, their bodies are able to make Vitamin D with the help of sunlight. Vitamin D, a vitamin found in fish oil, is necessary to prevent rickets, a bone disease caused by too little calcium."

"In contrast, in Africa, which is near the equator, indigenous humans require intense sunlight to penetrate their dark skin to make Vitamin D. This is all well and good. However, when blacks lived in England during the Industrial Revolution, they were the first to develop symptoms of rickets, such as retarded growth, bowed legs and fractures because not enough sunlight was available."

"Fortunately, in 1930, Vitamin D was discovered and dispensed as a supplement to add to the diet."

The most recent scientific evidence indicates that all humanity originated in Africa. It is most likely that the first people had relatively large numbers of eumelanin producing melanocytes and, accordingly, darker skin (as displayed by the indigenous people of Africa, today). As some of these original peoples migrated and settled in areas of Asia and Europe, the selective pressure for eumelanin production decreased in climates where radiation from the sun was less intense. Thus variations in genes involved in melanin production began to appear in the population, resulting in lighter hair and skin in humans residing at northern latitudes. Studies have been carried out to determine whether these changes were due to genetic drift or positive selection, perhaps driven by requirement for vitamin D. Of the two common gene variants known to be associated with pale human skin, Mc1r does not appear to have undergone positive selection, while SLC24A5  has.

As with peoples that migrated northward, those with light skin who migrate southward acclimatize to the much stronger solar radiation. Most people's skin darkens when exposed to UV light, giving them more protection when it is needed. This is the physiological purpose of sun tanning. Dark-skinned people, who produce more skin-protecting eumelanin, are less likely to suffer from sunburn and the development of melanoma, a potentially deadly form of skin cancer, as well as other health problems related to exposure to strong solar radiation, including the photodegradation of certain vitamins such as riboflavins, carotenoids, tocopherol, and folate.

Higher eumelanin levels also can be a disadvantage, however, beyond a higher disposition toward vitamin D deficiency. Dark skin is a complicating factor in the laser removal of port-wine stains. Effective in treating fair skin, lasers generally are less successful in removing port-wine stains in Asians and people of African descent. Higher concentrations of melanin in darker-skinned individuals simply diffuse and absorb the laser radiation, inhibiting light absorption by the targeted tissue. Melanin similarly can complicate laser treatment of other dermatological conditions in people with darker skin.

Freckles and moles are formed where there is a localized concentration of melanin in the skin. They are highly associated with pale skin.

Melanin in the eyes helps protect them from ultraviolet and high frequency visible light; people with blue eyes are more at risk for sun-related eye problems. Further, the ocular lens yellows with age, providing added protection.

Physical properties and technological applications
Absorption spectrum of melanin

Melanin is a biopolymer and a neuropeptide. In the early 1970s, researchers found melanin to be an organic semiconductor (Science, vol 183, 853-855 (1974)). Studies revealed that melanin acted as an electrical threshold switch, emitting a flash of light&mdash; electroluminescence&mdash; when it switched. Though the findings were published, these findings largely were ignored. Melanin also shows negative differential resistance, a classic property of electronically active, conductive, organic polymers. In 2000, the Nobel Prize in Chemistry was awarded to three scientists for their later 1977 work in the discovery and development of conductive polymers. The polymers utilized in this research were "polyacetylene black" melanins.

The original discoverers of switching and high electrical conductivity in melanin and related organic semiconductors were not honored in 2000. However, their melanin organic electronic device is now in the Smithsonian Institution's National Museum of American History's "Smithsonian Chips" collection of historic solid-state electronic devices. Melanin influences neural activity and mediates the conduction of radiation, light, heat and kinetic energy. As such, it is the subject of intense interest in biotech research and development, most notably in organic electronics (sometimes called "plastic electronics") and nanotechnology, where dopants are used to dramatically boost melanin conductivity. Pyrrole black and acetylene black are the most commonly studied organic semiconductors.

Although synthetic melanin (commonly referred to as BSM, or "black synthetic matter") is made up of 3-6 oligomeric units linked together - the so-called "protomolecule" - there is no evidence that naturally occurring biopolymer (BCM, for "black cell matter") mimics this structure. However, since there is no reason to believe that natural melanin does not belong to the category of the polyarenes and polycationic polyenes, like pyrrol black and acetylene black, it is necessary to review all the chemical and biological analytic data gathered to date in the study of natural melanins (eumelanins, pheomelanins, allomelanins)." Evidence exists in support of a highly cross-linked heteropolymer bound covalently to matrix scaffolding melanoproteins (Eur. J. Biochem. 1995; 232: 159-164 "Interaction of melanosomal proteins with melanin). It has been proposed that the ability of melanin to act as an antioxidant is directly proportional to its degree of polymerization or molecular weight (Ophthalmic research, 2005, 37: 136-141 "Melanin aggregation and polymerization: possible implications in age related macular degeneration"). Suboptimal conditions for the effective polymerization of melanin monomers may lead to formation of lower-molecular-weight, pro-oxidant melanin that is has been implicated in the causation and progression of macular degeneration and melanoma. (Clinical Cancer Res. 2004; 10: 2581-2583 "Etiologic pathogenesis of melanoma: a unifying hypothesis for the missing attributable risk"). Signaling pathways that upregulate melanization in the retinal pigment epithelium (RPE) also may be implicated in the downregulation of rod outer segment phagocytosis by the RPE. This phenomenon has been attributed in part to foveal sparing in macular degeneration. (Mol. Vis. 2005; 11: 482-490 "Melanization and phagocytosis: implications for age-related macular degeneration).

Melanin-based bias in human societies
When skin pigmentation as a characteristic of race becomes significant in some way, this phenomenon is known as racialism. Many people and societies overlay racialism with racist perceptions and systems which arbitrarily assign to groups of people a status of inherent superiority or inferiority, privilege or disadvantage based on skin color or racial classification. Apartheid-era South Africa is an example of a white supremacist society based on a system of stratification of power and privilege by skin color, as well as racial admixture. Similar examples can be found in India's caste system; Brazil's highly socially color-stratified society; and, in the U.S., segregation and institutional racism on the part of white-controlled institutions, and internal "color consciousness" on the part some ethnic minorities. Prejudice against people with more highly pigmented skin is the most pervasive form of color bias. Many other societies remain informally divided on the basis of skin color and, often, related ethnicity. (See also colonialism, Nazism, pigmentocracy and institutional racism.) Various presumptions about people with regard to hair color are far less common than skin-color bias, have far fewer and less serious real-world implications, and are more often applied to women than to men. Common stereotypes in the West are dumb blondes, hot-tempered redheads and vixen brunettes.