What is a Vitamin?

Image from Freepik.com

Before we look at vitamin A and vitamin D, it is good to first ask ourselves what exactly a vitamin is. Or rather: what it should be. The term 'vitamin' was coined in 1912 and has been very valuable in the acceptance of a new idea at the time, namely that nutrition is more than just proteins, carbohydrates and fats. It was a Dutchman who provided the proof for this revolutionary idea. Gerrit Grijns showed that the digestion of carbohydrates from rice (the starch from the grain) also required a minute amount of a substance from the hulls. This substance was able to prevent the tropical disease beriberi and was therefore called the anti-beriberi factor. It was the first in a series of “factors” of associated deficiency diseases.

Textbox: the discovery of the vitamin

The 19th century was a time of food shortages, poverty, hunger and disease. It was also the time of Dutch imperialism. The area we now call Indonesia was then the colony of the Dutch East Indies. At the end of the nineteenth century, the Dutch physician Christiaan Eijkman (1858 – 1930) left for the colony on a government assignment to investigate the cause of beriberi.

Eijkman used chickens as test animals, but he was unable to transmit the disease from beriberi sufferers to the animals through infection. Yet chickens from both the test group and the control group suddenly became ill. A while later, the symptoms disappeared again. Eijkman's laboratory was located on the grounds of the military hospital, where the chickens were fed the luxurious, cooked white rice left over from the kitchen.

Christiaan Eijkman found that the symptoms disappeared when the chickens were also given bran, the husks of rice. Eijkman made his discovery in 1897 but could not provide a good explanation for what he had found. His assistant Gerrit Grijns thought that the membranes might contain a substance essential for metabolism. After spending years ruling out other possibilities, he was left with no other explanation. Grijns described his finding in 1901 in the Medical Journal for the Dutch East Indies.

Er blijft ons dus geen andere weg open, dan te erkennen dat de gewone eisch aan een voedingsmiddel gesteld, het bevatten van een zeker kwantum verteerbaar eiwit, koolhydraten en vetten, niet voldoende is. ¹⁾

There is therefore no other way open to us than to recognise that the usual requirement for a food product, namely to contain a certain quantity of digestible protein, carbohydrates and fats, is not sufficient.

Gerrit Grijns was right. He is the real discoverer of vitamins. But he did not receive the Nobel Prize for it. Not even the theory is attributed to him. In 1906 Frederick Gowland Hopkins made his legendary statement during a lecture in London that would go down in history as the vitamin theory:

No animal can live upon a mixture of pure protein, fat, and carbohydrate, and even when the necessary inorganic material is carefully supplied the animal still cannot flourish. The animal body is adjusted to live either upon plant tissues or the tissues of other animals, and these contain countless substances other than the proteins, carbohydrates, and fats. ²⁾

A short time later it was decided to designate vitamins with letters and to call the substance vitamin B from now on. We now know it as vitamin B1, because it turned out that a whole complex of substances played a role. The numbered B vitamins are mainly cofactors required for all kinds of enzymes. That role explains why so minutely little of a vitamin is needed; After all, the enzymes themselves do not participate in the metabolic reactions. They are not consumed. And the hulls contain so little that hundreds of kilos of it were needed to isolate that one substance, that first discovered vitamin!

It was also in 1912 that Norwegian researchers discovered that the disease scurvy was probably caused by the lack of an anti-scurvy substance. We now know that substance as vitamin C or ascorbic acid. Isn't it remarkable that the first two vitamins discovered do not bear the first letters of the alphabet? That is thanks to the inventor of the vitamin alphabet, Elmer McCollum. He claimed the first letter as his own and also the discovery of vitamin A. The letters B and C were for the already discovered water-soluble vitamins, while vitamin A was fat-soluble. Later he discovered a second “fat-soluble vitamin” and logically that became vitamin D. A hundred years later his behavior still raises questions. The journey of discovery of vitamins was probably less elegant than it is often portrayed.

Textbox: the scientific misconduct by Elmer McCollum

In the famous 1912 article, Casimir Funk first coined the term “vitamin”. In the article, Funk discusses the diseases beriberi, scurvy and pellagra. Three common diseases that seemed to be deficiency diseases. There was a lot of searching for the missing substances that would cause the respective diseases. In his article, Funk also mentions rickets as a possible deficiency disease and encourages vitamin experiments to investigate this. He does mention that far too little is known about the enzymes and hormones that most likely arise from vitamins: ⁶⁾

I think that experiments with vitamines, which can at least do no harm, ought to be performed here in order to ascertain if a deficiency of the latter is not the real primary cause of the disease.

It is obvious that the minute amount necessary cannot be considered from the point of view of food. It is most probable that they are used as such or transformed into substances which are able to act in small quantities.

When Casimir Funk proposed the term “vitamine” in his scientific paper of 1912, he was looking for a term that sounded good and that would suit everyone. The term may not have been entirely accurate (as no “amines” were found) but it helped in the acceptance of the idea of deficiency diseases. It also helped to create a rapidly growing vitamin industry that was unhindered by regulation. The term seems to have lost none of its power and is inextricably linked to health and vitality.

Textbox: the successful marketing thanks to Casimir Funk

With his term “vitamine”, Funk clearly referred to the micronutrient itself and not to the enzyme or hormones produced by the body for which that vitamin is needed. In 1970, Nobel laureate ⁹⁾ Paul Greengard defined a vitamin as follows:

A vitamin may be broadly defined as a substance that is essential for the maintenance of normal metabolic functions but is not synthesized in the body and, therefore, must be furnished from an exogenous source. ¹⁰⁾

Textbox: Paul Greengard's statements

With today's knowledge we must conclude that vitamin A and vitamin D are not in line with Funk's intentions, nor do they meet Greengard's definition. They are both substances that are produced by the body itself. For vitamin A, it turned out a few years after its discovery that the substance that does meet the definition is vegetable carotene.

Both retinol (vitamine Aplugin-autotooltip__default plugin-autotooltip_bigThe term “vitamin A” is often used for the group of substances from that metabolism, the vitamin A metabolism. On this website, with vitamin A the substance retinol is always meant.) and cholecalciferol (vitamine Dplugin-autotooltip__default plugin-autotooltip_bigThe term “vitamin D” is often used for the group of substances from that metabolism, the vitamin D metabolism. On this website, with vitamin D the substance cholecalciferol is always meant.) are part of internal regulatory systems. These systems ensure that the body's own production is limited. However, if these substances are added excessively from outside, via the diet or through “supplementation”, then the regulatory systems that limit the body's own production are bypassed and blood values can rise too high.

In addition, the determination of the blood value for vitamin D is based on an incorrect assumption. Rather than measuring the concentration of vitamin D in the blood, a derivative is determined, namely the value of the substance 25-hydroxyvitamin D (25-D). It is assumed that this value is a measure of the actual vitamin D in the blood. A direct clinical vitamin D determination (of colecalciferol) is not available. However, the concentration of 25-D does not have a one-to-one relationship with that of vitamin D. It is therefore not a certain reflection of vitamin D in the blood. Studies have shown that the value of 25-D can be downregulated by disease processes. If this happens, it gives a false impression of a “deficiency”. ¹¹⁾¹²⁾

Vitamin A and vitamin D are both highly toxic. As far back as the 1920s, when the substances were discovered, researchers warned about their deadly dangers in cod liver oil (see box). They always used this oil from fish livers in research into the two fat-soluble vitamins. It was not until around 1930 that it became clear that vegetable carotene was the actual source of vitamin A in the livers. Ergosterol from plants or vegetable oil was thought to be the source for vitamin D.

Textbox: deadly vitamins

In 1929, Thomas Moore wrote in the leading journal The Lancet that -very likely- carotene from carrots is converted into vitamin A in the laboratory animal. In 1930, Moore followed up with a report in which he confirmed his discovery. ¹⁷⁾¹⁸⁾

Now you might think: great, the real vitamin was found! And using the toxic livers from cadavers was a mistake. Better half-turned than completely gone astray! That's how it seemed to go at first. But what eventually followed was a 180-degree turn.

In 1931, the standards for vitamin A and vitamin D were established. This was important for trade and industry, for example to be able to assess vitamin preparations. The standard for vitamin A was then based on the safe carotene, the plant source. The substance ergosterol was assumed to be the plant form source of vitamin D and chosen as its standard.

This all remained the case until after the Second World War the newly established World Health Organization took over the task of standardization. Since then, the standards have been based on the body's own substances that were known to be toxic. A few years earlier, the issuance of Recommended Dietary Allowances had already begun, in which safe dosages were laid down. A remarkable twist.

Textbox: the creation of the standards

In 1931, the first “International Conference on Vitamin Standards” took place in London, under the auspices of the League of Nations (which collapsed in 1946 with the advent of the United Nations). There, the standards were established for all vitamins. The standard for vitamin A was based on vegetable carotene. That of vitamin D on (UV-irradiated) ergosterol. However, ergosterol is a myco-sterol, a sterol from the fungi with which plants are contaminated. ¹⁹⁾ At the second meeting in 1934, the standard for vitamin A was improved and pure beta-carotene was designated as the basis.

The 1940s saw the creation of several important new organizations:

1940: the Food and Nutrition Board, a U.S. government agency,
1941: the Nutrition Foundation, an initiative of the U.S. food industry,
1945: the United Nations, a worldwide diplomatic and political organization,
1948: the World Health Organization of the United Nations.

The Food and Nutrition Board would henceforth establish the Recommended Dietary Allowance (RDA) for vitamins. In 1941, the first RDA was presented at the National Nutrition Conference for Defense. In 1949, the WHO General Assembly met for the first time and the standards for vitamins were amended. The standard for vitamin A was changed from beta-carotene to an ester of vitamin A (which in the meantime could be synthesized). The basis for the standard for vitamin D from now on became cholecalciferol. ²⁰⁾

Changing the standard for vitamin A by the WHO in 1949 was no easy task. A committee was set up to determine the conversion factor from beta-carotene to vitamin A. The report published in 1951 on the proceedings is hilarious. The proposals had gone in all directions and there had been much disagreement between parties.

From the other side of the Atlantic, it appeared that vitamin A was lost in the Atlantic, for it started out labelled with a certain value in U.S.P. units, but on arrival in England was labelled with a smaller number of international units in spite of the fact that no difference between the value of these two units could be officially recognized in the United States. Goodwill overcame the difficulties somehow and we got our vitaminized margarine. ²¹⁾

Establishing the correct ratio had proven to be an utterly impossible task. The committee was therefore very relieved when, with help from America, a compromise was reached.

We were greatly relieved to feel that we had not to undertake yet another collaborative investigation. ²²⁾

But if we consider that our body itself limits the conversion of beta-carotene to vitamin A (it will not poison itself) then we can understand how unlikely it is that such a fixed ratio can be found. The body simply down-regulates the conversion as soon as a certain level is present in the blood. The conversion is a controlled feedback system. ²³⁾

All this time, the toxic effects of vitamin A (retinol) and vitamin D (cholecalciferol) were well known. Charles Glen King was appointed as the first scientific director of the Nutrition Foundation, founded by the food industry. In 1976, he published the book A Good Idea about the history of the foundation. In it, he acknowledges the toxicity and also the incidents that had occurred, but as an explanation he refers to the limited understanding of the public. More control by the FDA would be necessary to protect the people from their ignorance. In passing he makes the comparison of vitamin A with table salt and water. 😳

Compare the hazard classifications yourself:

From the 1970s onwards, research into vitamin A and vitamin D took a number of unexpected turns. It turned out that many more substances were involved in these metabolisms; for both vitamin A and vitamin D, a chain of different metabolites appeared to ensure the final effect. Then the signalling effect also came as a surprise: it meant that suddenly there were steroid and retinoid hormones. ²⁴⁾²⁵⁾²⁶⁾²⁷⁾

But eventually it was discovered that vitamin A and vitamin D both play a crucial role in gene expression, translating our hereditary material into the corresponding proteins. For example, the building blocks for the skeleton, or enzymes, or antibodies. Disrupting that genetic system can have far-reaching consequences. A disruption during embryonic development gives rise to the risk of birth defects. Disruptions during growth and early development pose a risk of abnormalities in, for example, the musculoskeletal system or teeth. Later in life, a disrupted system can lead to all kinds of different chronic diseases and immune dysfunction. More than 500 target genes have been found for vitamin A. For vitamin D there are at least 913, but possibly even thousands of target genes. Both vitamins are inextricably involved in gene expression. ²⁸⁾²⁹⁾³⁰⁾³¹⁾

Textbox: the teratogenic effects of vitamin A

At the end of the 20th century, vitamins A and D appeared to work very differently than previously assumed. The puzzle of vitamin A and vitamin D turned out to be much more complex than it had seemed a hundred years earlier.

What is a Vitamin?

The Discovery

Powerful Term

Standards and Interests

Genetic Disruptions