Discovery and Characterization of Vitamin D: A Milestone in Nutritional Science

The early 20th century marked a pivotal period in the understanding of vitamins, particularly the discovery and characterization of vitamin D. The groundwork for this discovery was laid by Sir Edward Mellanby in 1919/20 when he conducted groundbreaking experiments to investigate the cause of rickets, a bone disease that was prevalent at the time. Mellanby’s work involved raising dogs in an environment devoid of sunlight or ultraviolet light, thereby mimicking conditions that could lead to rickets. He meticulously devised a diet that allowed him to determine that rickets was indeed caused by a deficiency of a trace component in the diet. This crucial finding was a significant step forward in understanding the role of nutrition in preventing disease.

In 1921, Mellanby published his findings, stating, "The action of fats in rickets is due to a vitamin or accessory food factor which they contain, probably identical with the fat-soluble vitamin." This statement was revolutionary, as it suggested that rickets could be prevented by a dietary component found in certain fats, particularly cod liver oil. Mellanby’s identification of cod liver oil as an excellent antirachitic agent was a milestone in nutritional science, as it provided a practical means of preventing rickets through dietary supplementation.

Mellanby’s work laid the foundation for further research into the fat-soluble vitamins. Shortly after Mellanby’s discovery, E.V. McCollum and his associates conducted experiments that distinguished between two fat-soluble vitamins, vitamin A and vitamin D. By bubbling oxygen through a preparation of the "fat-soluble vitamin," they observed that vitamin A was inactivated, whereas vitamin D retained its activity. This distinction was critical in understanding the specific roles of these vitamins in human health.

The identification of the role of sunlight in vitamin D production came soon after. In 1923, Goldblatt and Soames made a breakthrough discovery when they identified that 7-dehydrocholesterol, a precursor of vitamin D found in the skin, could be converted into an active form of vitamin D when exposed to sunlight or ultraviolet light. This finding provided a biological explanation for the protective effect of sunlight against rickets, further cementing the connection between sunlight exposure and vitamin D synthesis.

Hess and Weinstock later confirmed this connection through an innovative experiment. They excised small portions of skin from rats, irradiated the skin with ultraviolet light, and then fed it to groups of rachitic rats. The irradiated skin provided absolute protection against rickets, while the unirradiated skin did not, conclusively demonstrating that irradiated skin could produce sufficient quantities of vitamin D to prevent rickets. This experiment also suggested that vitamin D might not be an essential dietary trace constituent, as it could be synthesized in the body through exposure to light.

In parallel studies, Steenbock and Black discovered that food irradiated with ultraviolet light also acquired antirachitic properties. This finding underscored the importance of vitamin D in preventing rickets and further solidified its classification as a vitamin. The rapid advances in nutritional science during this period, particularly the identification of water-soluble and fat-soluble vitamins, played a crucial role in establishing vitamin D as a key nutrient necessary for bone health and the prevention of rickets.
Discovery and Characterization of Vitamin D: A Milestone in Nutritional Science

Discovery and history of niacin

Recognition that niacin is a vitamin in the early 20th century resulted from efforts to understand and treat a widespread human disease – pellagra.

Pellagra was probably first observed in 1735 in Asturias, autonomous community in Kingdom of Spain.

It was identified among the peasants by Don Gaspar Casal in 1735, soon after the maize was introduced into Europe. A loathsome skin disease, it was called “mal de la rosa” and often mistaken for leprosy.

Pellagra was already an epidemic in Europe in the 18th century, and in the first half of the 20th century it also started its spread in the United States of America, particularly among the poorest social classes.

In 1915, American epidemiologist and US Public Health Service officer Joseph Goldberger conducted a series of experiments on 11 healthy volunteer prisoners in a Mississippi jail and found that he could induce pellagra by altering their diets. He concluded that the disease was caused by the absence of some factor that was lacking in corn. He named it the P-P (for pellagra-preventative) factor.

In 1937, American biochemist Conrad Arnold Elvehjem and his colleagues successfully isolated the vitamin and demonstrated that pure nicotinic acid and nicotinic acid amide would reverse the pellagra and black tongue in dogs by feeding them the Goldberger diet.

He also isolated the P-P factor from active liver extracts, showing that this factor is actually nicotinic acid (subsequently named niacin for nicotinic acid vitamin).

The discovery of niacin as the antipellagra vitamin was announced by C. A. Elvehjem, R. J. Madden, F. M. Strong, and D. W. Woolley in 1937 (J. Am. Chem. Xoc. 59, 1767 (1937)),

During the following year a number of clinical trials were made which established beyond doubt the value of niacin in the treatment of pellagra, and that the acid or its amide should be regarded as the P-P (pellagrapreventive) factor.
Discovery and history of niacin

Discovery of riboflavin

The British chemist Alexander W. Blyth in 1879 isolated from milk whey a water-soluble, yellow fluorescent compound he called lactochrome, appropriately named for its color and origin. ‘Lacto’ from the milk and ‘chrome’ meaning color because of the yellow pigment.

The search to identify these accessory food factors in milk, whole wheat, yeast, and liver began in the early 1900s.

McCollum and assistant Marguerite Davis produced three papers in 1915 which showed a diet containing 2% of wheat embryo or milk powder with polished rice, casein, salts, and butter fat provided enough of an ‘essential accessory’ to support growth of young rats.

The importance of lactochrome was not fully realized until later investigational studies by Elmer McCollum and Kennedy (1916), Emmett and Luros, and Smith and Hendrick that showed the preventive capabilities of water-soluble food extracts against beriberi, pellagra, and pellagra-like dermatitis.

Several years later, the physiological role of the yellow growth factor was shown by Warburg and Christian (1932) to be a component of a yeast “Zwischenferment,” which was designated the “old yellow enzyme.”

Joseph Goldberger in 1927 proposed there was an anti-pellagra factor in eggs, milk, etc., and it was the same substance as ‘water-soluble B’ identified by McCollum. Goldberger called the substance the pellagra-preventative or P-P dietary factor.

In 1935 Richard Kuhn at Heidelberg, and Paul Karrer at the University of Zurich eventually succeeded in synthesizing the vitamin, now termed riboflavin. They were awarded the Nobel Prize for this and other achievements in 1937 and 1938, respectively. Kuhn first proved that riboflavin is an essential growth factor, viz., vitamin B2.

Kuhn also developed a synthetic route to riboflavin which was licensed to the German company I. G. Farben.

Theorell in 1937 identified the isoalloxazine derivative from the old yellow enzyme as riboflavin-5′-phosphate, also called FMN (flavin mononucleotide). The structure of a second coenzymic form was established by Warburg and Christian (1938) as FAD (flavin adenine dinucleotide) and was shown to participate as the coenzyme of d-amino acid oxidase.
Discovery of riboflavin

Elmer McCollum - Discovering Vitamin A, Vitamin B and Vitamin D

Elmer Verner McCollum (March 3, 1879 – November 15, 1967) was born and raised in Kansas and attended the University of Kansas. His studies were initially directed toward medicine, but he eventually decided that chemistry better captured his interests, and he completed his work for a Masters degree in chemistry at Kansas. He was accepted into the Ph.D. program at the Sheffield Scientific School at Yale.

Contrary to the dogma that all fats had similar nutritional value, in 1913, Elmer McCollum and his associate Marguerite Davis at Wisconsin showed butter and egg yolk were not equivalent to lard and olive oil in supporting the growth and survival of rats. The growth-supporting ‘accessory factor’ became known as ‘fat-soluble A’ in 1918 and then ‘vitamin A’ in 1920.

“Fat-soluble A” was first believed to be a single vitamin capable of curing xerophthalmia and rickets. Cod-liver oil was first used as a therapeutic agent in the 1770s. McCollum showed that cod-liver oil aerated at the temperature of boiling water for 12 to 20 hr retained its antirachitic activity in rats, but was ineffective against xerophthalmia. In addition, these properties were unequally distributed in certain foods. Apparently, two separate factors were involved. The factor effective against rickets later was named vitamin D.

The discovery of vitamin A by McCollum and Davis in 1913 ushered in the era of accessory food substances culminating in the achievement of that goal. It included the discovery of vitamin D and its production in skin caused by ultraviolet light. This was followed by a description of its actions at the physiological level that resulted in a healthy skeleton and beyond.

In 1915 McCollum and Davis had found that when water oralcohol extractions of wheat germ or rice polishing were added, polished rice was greatly improved in nutritional quality. These experiments constituted the basis for their discovery that the anti-beriberi factor, necessary to relieve polyneuritis in pigeons, was necessary for rats and that there were apparently only two unidentified nutrients necessary for such animals.

They proposed the term fat-soluble A and water-soluble B, respectively, to designate the two unidentified nutrients. The isolation of B1was achieved in 1926 by Dutch scientists in Java using small “rice birds” fed on washed white rice supplemented with cod liver oil for their assays.

Elmer McCollum - Discovering Vitamin A, Vitamin B and Vitamin D

Discovery of Vitamin B12

By the late 1940s, Combs and Norris using chick growth as their bioassay procedure were fairly close to the isolation of vitamin B12.

In 1926, Vitamin B12 was discovered by two physician George Richard Minot and William Perry Murphy became inspired by George Whipple’s studies that showed daily beef liver a pound could indeed control the deadly anemia.

Minot and Murphy of Harvard showed that feeding the large amounts of raw liver, that is a quarter to half a pound per day, restored the normal level of red blood cells in cases of pernicious anemia.

Following this discovery and for the next twenty years, liver was the main source of this unknown curing factor, which has prepared, as time passed, in more and more concentrated form.

In 1929, William B. Castle of Harvard hypothesized that the liver was the organ of the body contained a factor essential for the cure of pernicious anemia.

Its chemical structure as elucidated in 1955, through the collaboration of chemists from the University of Cambridge, led by Alexander Todd, with X-ray crystallographers from the University of Oxford, led by Dorothy Hodgkin and a team from Glaxo led by Lester Smith.

However, Vitamin B12 only finally synthesize by Robert Burns Woodward in 1971.
Discovery of Vitamin B12

Discovery of Vitamin B

The Englishman Sir Frederick Gowland Hopkins is given credit for approaching the discovery of the vitamin concept, when in 1906, he determined that food contains essential ingredients beyond carbohydrates, minerals fats, proteins and water.

The term vitamin was first used for water soluble substance which was necessary for the nutrition of infants and which was separated from wheat germ, yeasts and milk.

In fact this term was used after the first discovery of anti-beriberi factor by Casimir Funk in 1912. The first vitamin B discovered was vitamin B1 by Funk that was extracted from police rice husk.

It was then isolated in pure and crystalline form by B.C.P Jansen in 1925.

Casimir coined the term ‘vital amine’ to describe the class of chemicals that he and other researchers were studying, and the word was simplified to ‘vitamin’ by 1920.

Three years after this discovery, Elmer Vernon McCollum and Marguerite Davis labeled it ‘water soluble B’ which British biochemist Jack Cecil changed to vitamin B in 1920.

Casimir Funk (1884-1967), a Polish born American biochemist, collected all published literature in the issue of deficiency diseases. He was the first to isolate niacin, latter called vitamin B3.
Discovery of Vitamin B