The Journey of Discovery: A Historical Perspective on β-carotene

β-carotene, a pivotal precursor to vitamin A, holds a profound significance in the realm of nutrition and biochemistry. Its narrative unfolds through a series of meticulous experiments and groundbreaking revelations by pioneering scientists, each contributing to our understanding of its properties and role in human health.

The inception of β-carotene's journey dates back to 1831 when Heinrich Wilhelm Ferdinand Wackenroder crystallized it from carrots. Little did he know that his discovery would pave the way for future advancements in nutritional science. Wackenroder's doctoral dissertation on anthelminthics in the vegetable kingdom, published in 1826, foreshadowed his later work and earned him prestigious recognition, setting the stage for his subsequent research endeavors.

In 1847, William Christopher Zeise, a Danish organic chemist, recognized β-carotene's hydrocarbon nature, although his analyses initially yielded a composition of C5H8. It wasn't until 1886 when Léon-Albert Arnaud confirmed its hydrocarbon nature and proposed a formula close to the theoretical composition of C40H56, a milestone achievement acknowledged by the French Academy of Sciences.

The definitive empirical formula of β-carotene, C40H56, was established in 1907 by Willstatter and Mieg, marking a significant leap forward in our comprehension of its chemical composition. However, the true elucidation of its structure awaited the pioneering work of Paul Karrer in 1930-31. Karrer's extraction of vitamin A from cod-liver oil and determination of its composition marked a watershed moment, earning him a Nobel Prize and establishing a foundational framework for future research in the field.

The link between β-carotene and vitamin A remained elusive until 1919 when Steenbock proposed a potential relationship between the two. However, it wasn't until 1965 that Jim Olson and DeWitt Goodman independently demonstrated the formation of retinal, the aldehyde form of vitamin A, from β-carotene in cell-free extracts of liver and intestine. This groundbreaking revelation shed light on the vital pathway of β-carotene metabolism, cementing its status as a crucial precursor to vitamin A and revolutionizing our understanding of its physiological role.

In conclusion, the history of β-carotene is a testament to the relentless pursuit of scientific inquiry and the cumulative efforts of visionary researchers. From its serendipitous discovery in carrots to the elucidation of its chemical structure and metabolic pathways, β-carotene's journey exemplifies the transformative power of scientific discovery in shaping our understanding of nutrition and human health.
The Journey of Discovery: A Historical Perspective on β-carotene

Pellagra: History and Discovery

Pellagra, arising from insufficient niacin intake, derives its name from the Italian phrase "pelle agra," translating to rough skin. Originating in the Lombard dialect of Northern Italy, this term underscores the condition's most prominent clinical feature.

In 1735, Spanish physician Don Gaspar Casal identified pellagra among peasants in Spain's Asturia region, labeling it "mal de la rosa." This ailment exhibited classic symptoms like dermatitis, diarrhea, and dementia, often resulting in fatality. Casal's posthumous work in 1762 extensively elaborated on the condition, using a Spanish term that echoed the characteristic sunburn-like skin erythema associated with pellagra.

The initial documented cases of the disease in 1755 and 1762 provided an accurate description, linking it to spoiled maize. Pellagra emerged in Italy approximately 50-100 years later, persisting widely in the country during the nineteenth century, with Lombardy reporting 39,000 cases in 1862. Serbia and Southern Russia grappled with the disease in the early 20th century.

The term "pellagra" likely made its debut in 1771 in Milan, Italy, coining the name that denotes "rough skin." Frappoli in 1771 proposed the term, possibly tracing its origins to the "pellarella" documented in Milan in 1578.

In the first half of the 19th century, societal aspects of pellagra gained attention, particularly in Liberali's 1831 studies on the manic dementia linked to the condition. Pellagra vanished from Southern France around 1880, and by 1916, it had nearly disappeared in Italy for reasons that remain unclear.

In 1922, Goldberger and Tanner suggested that pellagra resulted from an amino-acid deficiency. Joseph Goldberger, an American physician and epidemiologist, is acclaimed in American clinical epidemiology for his pellagra studies in the early 20th century.

The 1937 discovery that pellagra is caused by a deficiency in niacin (nicotinic acid), a B vitamin, highlighted that the body's synthesis of this vitamin depends on the availability of the essential amino acid tryptophan, found in milk, cheese, fish, meat, and eggs.
Pellagra: History and Discovery

Vitamin B5: History and discovery

Pantothenic acid, also known as pantothenate or vitamin B5, is a water-soluble B-complex vitamin. It is pantoic acid linked to β-alanine through an amide bond.

The presence of a pellagra-like dermatitis in chicks on a restricted diet was first described by Ringrose and Norris in 1931.

Pantothenic acid (also known vitamin B5) is a water-soluble B-complex vitamin that was identified in 1933. It was first shown to be an essential factor for the growth of yeast and in curing of (deficiency-induced) dermatitis in chickens.

Pantothenic acid was isolated and extracted from liver in 1938, and first synthesized in 1940. Roger John Williams is credited with coining the name from the Greek word panthos, which translates as “from everywhere.” It was given this name because of its widespread presence in food.

Williams an American biochemist, established that pantothenic acid was required for the growth of certain bacteria and yeast. Using chromatographic and fractionation procedures that were typical of the 1930s (solvent-dependent chemical partitioning), Williams isolated several grams of pantothenic acid for structural determination from 250 kg of liver.

In the 1950s, one of the functional forms of pantothenic acid, coenzyme A (CoA), was discovered as the cofactor essential for the acetylation of sulfonamides and choline.6 In the mid-1960s, pantothenic acid was next identified as a component of acyl carrier protein (ACP) in the fatty acid synthesis complex.
Vitamin B5: History and discovery

Roger J. Williams

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

Christiaan Eijkman and beriberi

During the time period of the Dutch beriberi problem in Indonesia, physicians were preoccupied with the concept that diseases were cause by pathological problem.

In 1886 Christiaan Eijkman and other physicians began the quest for identifying the beriberi microbe and developing procedures for eliminating the disease. As a former student of Robert Koch, he had been trying to isolate and infect chickens with ‘beriberi bacteria’.

Early discovery, which demonstrated the specificity of the dietary essentials, was Eijkman’s production of beriberi on chickens in 1897 by feeding them polished rice.

The polished cooked rice had resulted in beriberi symptoms of peripheral neuritis. This disease was prevented or cured by feeding either a diet of unpolished rice or a diet to which alcoholic extract of rice bran was added. Eijkman thought that a toxin in rice was being unmasked in the conversion of brown to white rice.

In 1901, Gerrit Grijns, Eijkman’s successor, observed that chicken fed on raw meat did not develop polyneuritis whereas those exclusively fed on meat that has been heated long enough at 120° C developed the disease.

After further work, his statement in 19o1 was perhaps the progenitor of the “vitamin era” in nutritional research: “There occur in various natural foods substances which cannot be absent without serious injury… they are easily disintegrated … and cannot be replaced by simple chemical compounds.”
Christiaan Eijkman and beriberi

The first scientific description of a vitamin D-deficiency by Dr. Daniel Whistler

The term ‘rickets’ first appeared in 1634 when listed as a cause of death in London’s Annual Bill of Mortality.

The first scientific description of a vitamin D-deficiency, namely rickets, was provided in the 17th century by both Dr. Daniel Whistler and Professor Francis Glisson.

It was that English physician Dr. Daniel Whistler described its symptoms in 1645. The publication by Whisker was a concise monograph of only 14 pages and was written when author was 26 years old. It represented the thesis required for his degree of doctor of medicine. His thesis was ‘De morbo perili Anglorum’ - The Children’s disease of the English.

The Latin thesis was read at Leiden on 18th October 1645. The importance of this thesis lies in the fact that it contained the first complete clinical account of rickets. Whistler's book was published a short time after the reading of his thesis in 1645. It was a small quarto volume of some eighteen pages, though when it was reprinted in 1684, it was in octavo.

In his thesis Dr. Whistler proposed a wide range of suggestions for treatment from crow’s or frog’s livers, application of leeches, purgation, poultices of snails and salt placed on the belly, and grease from mainly pork fat, goosegrease and butter to be smeared on the swollen epiphyses.
The first scientific description of a vitamin D-deficiency by Dr. Daniel Whistler

Discovery of Thiamine

Thiamine was the first vitamin to be discovered. Kanehiro Takaki, a Japanese naval doctor, was the first to report that beriberi seemed to be a nutritional deficiency based on reducing the incidence of beriberi in Japanese sailors by giving them additional meat, dry milk and vegetables.

Christiaan Eijkman, a Dutch military surgeon, who traveled to the Dutch East Indies to study beriberi, in 1890s began to clarify the role of diet in the development of beriberi.

Eijkman discovered that a disease similar to beriberi occurred in birds that were fed a diet of steam-cooked polished rice, as opposed to crude rice.

In 1926, thiamine was the first B vitamin isolated, as a crystalline, water soluble, yellowish white powder with a salty, slightly nutty taste. It was crystallized from rice polishing by two Dutch scientists Barend Jansen and W. F. Donald as antineuritic vitamin.

By 1936 it had been synthesized and its chemical structure determined by Robert R. Williams which he named ‘thiamine’.

The discovery of thiamine revolutionized the management of wet beriberi because thiamine quickly reversed the cardiac manifestations of the disease.
Discovery of Thiamine

Vitamin E in History

Vitamin E was discovered in 1922 by Evans and Bishop as an unidentified factor in vegetable oils required for reproduction in female rats.

The observation was published in 1922. First named ‘factor X’ and the ‘antisterility factor’, Evans suggested adopting the letter E to designate the factor following the then recognized vitamin D.

A vitamin E active compound was isolated from wheat germ oil in 1936.

Because this compound permitted an animal to have offspring, research group named the compound alpha-tocopherol from Greek word ‘tocos’ (meaning childbirth) and ‘ferein’ (to bring forth), relating to its essentiality for rats to bear young. To indicate the presence of an OH group in the molecule, ‘ol’ was added to the ending.

Its correct structure was given in 1938 and the substance was first synthesized by P. Karrer, also in 1938.

In 1940s, a team of Canadian physicians discovered that vitamin E could protect people from coronary heart disease.

Demand for vitamin E has rapidly increased. Along with market demand, the number of product types available to the pharmaceutical food, feed, and cosmetic industries has increased.

In 1968 the Food and Nutrition Boards of the National Academy of Sciences officially recognized vitamin E as an essential nutrient.
Vitamin E in History

Discovery of Biotin

The discovery of biotin and the eventual elucidation of its structure, as well as its role in metabolism, involved diverse investigation spanning many decades.

Early in the 1900s, it was observed that certain strains of yeast required a material called ‘bios’ for growth.

Biotin was the name given to a substance isolated from egg yolk by Kogl and Tonnis in 1936 that was necessary for yeast growth.

This substance was discovered to be identical to a growth factor named coenzymes R that was required by legume nodule bacteria.

The toxic properties of feeding raw egg white to animals were first observed by Bateman in 1927.

Clinical sign of dermatitis and hair loss due to egg white injury were prevented by several researchers by feeding certain foods, notably liver and kidney.

It was recognized in 1936 that this condition can be healed by biotin supplements.

Paul Gyorky, Hungarian biochemist, studied the chemistry of this protective factor in certain foods, which he named factor H in 1937.

In 1940 Gyorky and associates found that biotin, vitamin H and coenzyme R were the same substance.

Biotin was extracted from egg yolks, but is also to be found in yeast, liver and elsewhere.

The structure id biotin was determined by Dr. Vincent du Vigneaud in 1942, and the vitamin was synthesized soon after by Harris and co-workers in 1943.

Soon after the research into its chemistry, it was discovered that biotin in involved in biochemical carboxyl transfers.
Discovery of Biotin

History of Vitamins (Part II)

History of Vitamins (Part II)
Around 1900, the idea had been widely accepted that human beings and animals require very small amounts of additional nutritional factors (“accessory growth factors”), the lack of which leads to disease.

In 1912, C. Funk coined the vitamin. Funk experimenting in the area of dietary disease, and worked on the isolation of the anti-beriberi factor. Because he assumed that this and the other curative factors contain nitrogen, that is, are mines, he named them “vitamins” (vital amines).

In 1929, C. Eijkman and F. G Hopkins shared the Nobel Prize in Medicine for their discoveries in the area of vitamins.

Eijkman’s discovery that polished rice leads to polyneuritis in birds and beriberi in human beings prepared the way for the isolation of thiamin.

Hopkins showed, by experimenting on rats, that milk contains substances which, in very small amounts, make growth possible. In this way he extended the insights of Lunin and confirmed them with more complete experiments.

Almost none of the vitamins is a single substance. Instead, there are whole families of close chemical relatives which, however may differ greatly in their biological activity.

The substances which we call vitamins must usually be converted within the living cell to their coenzyme or hormone forms in order to become biological active. Fore example vitamin D is hydroxylated and aquacobalamin is methylated or adenosylated.

Vitamin deficiencies were formerly one of the main causes of illness and death. Pellagra, scurvy and beriberi are best known vitamin deficiency diseases.
History of Vitamins (Part II)

Casimir Funk: the Father of Vitamins

Casimir Funk: the Father of Vitamins
Vitamins are s much a part of modern life you may have a hard time believing they are first discovered less than a century ago.

Of course, people have long known that certain food contain something special.

For example, the ancient Greek physician Hippocrates prescribed liver for night-blindness (the inability to see well in dim light).

By the end of the 18th century (1795), British Navy ships carried a mandatory supply of limes or lime juices to prevent scurvy among the men, thus earning the Brits once and forever nickname limeys.

Later on, the Japanese Navy gave its sailors whole grain barley to ward off beriberi.

Everyone knew these prescriptions worked, but nobody knew why – until 1912, when Casimir Funk (1884 – 1967), a Polish biochemist working first in England and then in the United States, identified “something” in food that he called vitamins (vita – life; amines – nitrogen compounds).

The following year, Funk and a fellow biochemist, Briton Frederick Hopkins, suggested that some medical conditions such as scurvy and beriberi simply deficiency diseases caused by absence of a specific nutrient in the body.

Adding a food with the missing nutrition to one’s diet would prevent or cure the deficiency disease.
Casimir Funk: the Father of Vitamins

History of Vitamins (Part I)

History of Vitamins (Part I)
The development of the modern concept of vitamins can be roughly divided into three (broadly overlapping) periods:

1. Empirical healing of some diseases by administration of certain foods
2. Experimental induction of dietary disease in animals
3. Administration of synthetic diets to discover essential nutritional factors.
   
   

The first phase began many centuries ago, and gradually led to the recognition that night blindness, scurvy, beriberi and rackets are dietary diseases.

The ancient Greeks, Romans and Arabs healed night blindness with liver. In the 16th century, scurvy was healed using extracts of spruce needles, and in the 18th century, oranges and lemons were used; the issue of lemon juice to sailors in the English navy was required by law by the beginning of the 19th century.

At the end of the 19th century, the Japanese navy realized that beriberi was in someway connected with a diet of rice; the disease was successfully combated by replacing the rice with barley or by increasing the rations of meat and vegetables.

In the same period, it was learned that rickets could be prevented and cured by administration of fish liver oil.

The second phase was characterized by the used of experimental animals, in which dietary disease were deliberately induced and then healed.

The animal experiments made possible systematic study of diet related disease in human beings and animals.

In 1890, C. Eijkman discovered that polished rice, when given to chickens as their main food, caused polyneuritis (degeneration of the peripheral nerves).

This disease is similar to human beriberi.

Eijkman then demonstrated that non-polished rice or polished rice +rice bran, when given as feed, healed the polyneuritis.

These experiments led to the postulate that beriberi was caused by the lack of a nutritional substance.

Similarly, in 1907, A. Holst and T. Frohlich reported experimentally induce scurvy in guinea pigs and the healing of the condition by the same agents which are effective in human beings.
History of Vitamins (Part I)

Vitamin A in History

Vitamin A in History
Probably the first nutritional deficiency to be clearly recognized was night blindness. The ancient Egyptians, as indicated in the Papyrus Ebers and later in the London Medical Papyrus, recommended that juice squeezed from cooked liver topically applied to the eye to cure night blindness.

This writings date from 1500 BC, but the observations probably are of much earlier origin. The Greeks, who depended heavily on Egyptian medicine, recommended both the ingestion of cooked liver and its topical application as a cure for night blindness, a tradition that has persisted in many societies to his day.

Although interesting references to vitamin A deficiency and their cure can be found throughout history, the modern science of nutrition is only about a century old. The observation that experimental animals lose weight and die on purified diets was noted by many investigations toward the end of the nineteenth century.

In the early part of this century, specific factors necessary for growth and survival were beginning to be identified. Frederick Gowland Hopkins in England, for example, during the period 1906-1912 found that a growth stimulating principle from milk was present in an alcoholic extract of milk rather than in the ash.

During the same period, Stepp in Germany identified one of these “minimal quantitative factors” as a lipid. Soon thereafter, E. V. McCollum and Marquerite Davis in Wisconsin showed that butter or egg yolk, but not lard, contained a lipid soluble factor necessary for the growth of rats. In 1913 they coined the term “fat soluble A” and thereby attributed for the first time the growth stimulating property of these extracts to a single compound.

Approaching the problem is a very different way, Osborne and Mendel at Yale concomitantly found that cod liver oil or butter was an essential growth-promoting food for rats. The year 1913, therefore, was the beginning of the modern age of vitamin A exploration.
Vitamin A in History