Ann Nutr Metab 2012;61:192198
DOI: 10.1159/000343124
On the Discovery of Vitamin A
Richard D. Semba
Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Md., USA
Key Words
Crystallization Discovery Isolation Synthesis Vitamin A
Abstract
Vitamin A is essential for normal growth, reproduction, im-
munity, and vision. The characterization of vitamin A spanned
a period of about 130 years. During this long, incremental
process, there is no single event that can be called the dis-
covery of vitamin A. The physiologist Franois Magendie
conducted nutritional deprivation experiments with dogs in
1816 that resulted in corneal ulcers and high mortality a
finding similar to the common clinical situation in poorly fed,
abandoned infants in Paris. In the 1880s, Nicolai Lunin
showed that there was an unknown substance in milk that
was essential for nutrition. Carl Socin suggested that an un-
known substance for growth in egg yolk was fat soluble.
Frederick Gowland Hopkins proposed in 1906 that there
were unsuspected dietetic factors that were necessary for
life. In 1911, Wilhelm Stepp demonstrated that this essential
substance in milk was fat soluble. The following year, Hop-
kins showed that there were accessory factors present in
astonishingly small amounts in milk that supported life.
Contrary to the dogma that all fats had similar nutritional
value, in 1913, Elmer McCollum and Marguerite Davis at Wis-
consin and Thomas Osborne and Lafayette Mendel at Yale
showed butter and egg yolk were not equivalent to lard and
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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. Paul Karrer
described the chemical structure of vitamin A in 1932. Harry
Holmes and Ruth Corbet isolated and crystallized vitamin A
in 1937. Methods for the synthesis of vitamin A came with the
work of David Adriaan van Dorp and Jozef Ferdinand Arens
in 1946 and Otto Isler and colleagues in 1947. Further work
on the role of vitamin A in immunity and child survival con-
tinued until through the 1990s.
Copyright 2012 S. Karger AG, Basel
Introduction
Vitamin A is a fat-soluble substance that is essential
for normal growth, reproduction, immunity, and vision.
A great deal of confusion surrounds the discovery of
vitamin A. Who discovered vitamin A? When was it dis-
covered? Based upon a variety of authoritative nutrition
textbooks, popular sources, and sites on the World Wide
Web, there are over a dozen different answers to these
two simple questions. The contradictions arise because
the questions have a flawed premise. The objective of
this paper is to show the developments that led to the
characterization of vitamin A. I argue that it is impos-
sible to assign a moment of discovery of vitamin A in
129.215.17.190 - 6/16/2013 10:56:55 PM
Richard D. Semba, MD
University of Edinburgh
Johns Hopkins University School of Medicine
Smith Building, M015, 400 N. Broadway
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Baltimore, MD 21287 (USA)
E-Mail rdsemba@jhmi.edu

Fig. 1. Nicolai Lunin. Fig. 2. Frederick Gowland
Hopkins.
the long incremental process it took to characterize vi-
tamin A. The argument is presented in greater detail in
my book The Vitamin A Story: Lifting the Shadow of
Death (2012) [1].
Early Insights from Paris
In the early part of the 19th century in France, scien-
tists and philanthropists were seeking ways to feed the
restive poor in Paris. The population of Paris was grow-
ing rapidly; it almost doubled between 1800 and 1850.
The streets in some arrondissements were crowded with
beggars, rag-pickers, and thieves. A small increase in the
price of flour would ignite bread riots. Louis-Ren Vill-
erm (17821863), one of the founders of the public health
movement, showed that there were large disparities in
health between the rich and poor in Paris [2]. His col-
league, Louis-Franois Benoiston de Chteauneuf (1776 der physiologischen und pathologischen Chemie: Are
1856) reinforced the idea of health disparities when he
demonstrated that the average lifespan was longer among
the rich than the poor [3].
An inventor, Jean-Pierre-Joseph dArcet (17771844),
developed an efficient method for manufacturing gelatin
by processing bones [4]. Philanthropists seized upon the
idea of feeding gelatin to the poor in the form of a
soup both on the streets and in the hospitals of Paris.
Thus, to make knife handles or buttons from bones was
considered stealing from the poor [5]. Whether gelatin
made from leftover bones was a complete food was
fiercely debated. The patients who were forced to eat gel-
On the Discovery of Vitamin A
atin broth in the hospitals of Paris found it detestable and
nauseating, and complained that it could not sustain
them. Some patients died. Soon the hospital authorities
were obliged to stop serving gelatin. Thus, the fundamen-
tal question of what foods were nutritious rose from the
challenges of feeding the poor [1].
In 1816, a year notable for widespread crop failures
and famine across Europe, the physiologist Francois
Magendie (17831855) began a series of experiments
with dogs to evaluate the nutritional value of nitrogen in
foods [6]. When he fed a diet of sugar (containing no ni-
trogen) and distilled water to dogs, the animals grew
thin and developed ulcers on the cornea. The ulcers
eventually perforated, and the dogs died shortly there-
after. The pediatrician Charles-Michel Billard (1800
1832) took careful note of Magendies research. Billard
frequently observed similar corneal ulcers in abandoned
infants under his care in Paris, and he raised the ques-
tion whether these eye lesions could be related to defec-
tive nutrition [7].
Is an Unknown Fat-Soluble Substance Vital for Life?
In 1881, Nicolai Ivanovich Lunin (18531937) (fig.1),
in his doctoral research at the University of Dorpat in Es-
tonia, showed that adult mice could live in good health
on milk, but did not survive on a diet consisting of the
separate components of the milk. Lunin stated: Mice can
live quite well under these conditions when receiving
suitable foods (e.g. milk), however, as the above experi-
ments demonstrate that they are unable to live on pro-
teins, fats, carbohydrates, salts, and water, it follows that
other substances indispensable for nutrition must be
present in milk besides caseinogens, fat, lactose, and salts
[8]. Lunins mentor, Gustav von Bunge (18441920), re-
stated the question in his influential textbook Lehrbuch
there other substances in milk besides fats, albuminoid
matter, and carbohydrates necessary to the vital process-
es? [9]. A study of the different forms of iron in the diet
by another of Bunges students, Carl A. Socin, showed
that mice fed egg yolk alone lived for nearly 100 days,
while mice fed an iron-poor diet with or without other
forms of iron died within 1 month. Socin showed that
there was an unknown substance in egg yolk that was es-
sential to life, and he speculated that this was a fat-like
substance [10]. Bunge did not pursue this investigation,
as his main interests were related to the role of minerals
in nutrition.
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Ann Nutr Metab 2012;61:192198 193
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 Hopkins Proposes the Existence of Accessory Food
Factors
In 1906, the Cambridge biochemist Frederick Gow-
land Hopkins (18611947) (fig.2) spoke to the Society of
Public Analysts in London in a lecture titled The Analyst
and the Medical Man. Hopkins asserted that public ana-
lysts, i.e. those charged with protecting the food supply
by analyzing foods for adulteration, should extend the
scope of their work and study the composition of food
itself. Hopkins hinted at some dietary studies he had con-
ducted that suggested: no animal can live upon a mix-
ture of pure protein, fat, and carbohydrate, and even
when the necessary inorganic material is carefully sup-
plied the animal still cannot flourish [11]. The dogma of
the time, based upon the nutritional theories of Justus
von Liebig (18031873) and his contemporaries, was that
the only essential nutrients were protein, fat, carbohy-
drate, and minerals. Hopkins proposed that there were
unsuspected dietetic factors that accounted for condi-
tions such as rickets and scurvy.
One month after his talk in London, Hopkins pub-
lished a study in which he and his colleague Edith Will-
cock demonstrated the existence of the essential amino
acid tryptophan [12]. Hopkins had additional data about
unsuspected dietetic factors, but publication of these
findings was delayed due to illness. Paul Knapp (1874
1954), an ophthalmologist in Basel, continued Lunins
line of investigation with the nutritional qualities of milk
in 1909. He fed rats a diet of protein, carbohydrate, fats,
and minerals. The animals developed conjunctivitis and
corneal ulceration prior to death, but the eye disease and
mortality could be avoided if milk was provided in the
diet [13]. Knapp surmised that there might be something
in milk that prevented the eye lesions.
Hopkins eventually published his work on unsuspect-
ed dietetic factors in 1912. He reported that young rats
did not grow well when fed a basal ration of protein,
starch, cane sugar, lard, and minerals [14]. After a small
amount of milk was added to the basal ration, they had
normal growth. The unknown factors in milk that sup-
ported life were found in astonishingly small amounts
and were termed accessory factors by Hopkins. One
graph from the study shows the growth of rats that had
received the basal ration plus milk and the basal ration
alone (fig.3). After 18 days of the experiment, Hopkins
switched their diets so that the rats receiving the basal
diet plus milk no longer received any milk, and their
growth subsequently stopped by about 30 days. The rats
that received the basal diet alone grew poorly in the first
194 Ann Nutr Metab 2012;61:192198
80
Weight (g)
60
40
0 25 50
Time (days)
Fig. 3. Growth curves of mice in the experiments of Frederick
Gowland Hopkins. The lower curve shows the growth of 8 male
rats with the basal diet, indicated by open circles. At day 18 (ver-
tical broken line) the 8 rats were given 3 ml of milk per day, indi-
cated by dark circles. The upper curve shows the growth of 8
similar rats receiving the basal diet plus milk. At day 18, these 8
rats were crossed over to the basal diet only without any addi-
tional milk.
18 days of the experiment, but after they received milk
each day after the 18th day, they grew at a rapid rate. This
graph from the experiment became well known to stu-
dents and scientists, as it was subsequently reproduced in
many influential textbooks.
Hopkinss study was considered a landmark study in
the history of vitamins. Hopkins later received the Nobel
Prize in Physiology or Medicine in 1929, along with the
Dutch scientist Christiaan Eijkman (18581930) for the
discovery of the vitamins [15]. In his acceptance speech
in Stockholm, Hopkins humbly acknowledged that Lu-
nins study in 1881 already suggested the existence of
these unknown factors. Hopkins also referred to an ear-
lier study from Utrecht by Cornelis Pekelharing (1848
1922). Pekelharing stated that milk contained unknown
substances essential to life in mice but gave little experi-
mental details and no specific results [16]. Hopkins pro-
vided some early evidence for the existence of vitamins,
but his experiment was by no means definitive or spe-
cific. The nature of the accessory factors was not known,
and it was unclear in 1912 whether there were one or per-
haps many unknown essential factors in food.
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University of Edinburgh
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 Stepp Shows that a Fat-Soluble Substance in Milk Is
Necessary for Life
Wilhelm Stepp (18821964), a young medical graduate
working under the supervision of the German chemist
Franz Hofmeister (18501922), also conducted studies on
the nutritional properties of milk. He mixed flour with
milk and formed it into dough, which he called milk-
bread; this milk-bread mixture supported normal growth
in young mice. After the milk-bread was extracted with
alcohol and ether, mice could not survive beyond 3 weeks
on the extracted milk-bread. When the substance ex-
tracted with alcohol and ether was added back to the ex-
tracted milk-bread and fed to mice, they survived nor-
mally. In 1909, prior to the more widely known milk
study by Hopkins, Stepp concluded that a fat-soluble sub-
stance was essential for survival [17]. After further stud-
ies published in 1911, Stepp noted: certain lipid substanc-
es present in milk, soluble in alcohol-ether, are indispens-
able for the survival of mice [18].
American Investigators Show that Fats Are Not
Equal in Supporting Life
Thomas Osborne (18591929) and Lafayette Mendel
(18721935) conducted studies at Yale University that
were initially aimed at providing insight into the value of
proteins in the diet as summarized in their 1911 mono-
graph Feeding Experiments with Isolated Food-Substances
[19]. The following year, they noted: with respect to
the actual requirements of fat on the part of the healthy
organisms there is at present almost no definite informa-
tion available. Fats are, of course, commonly found pres-
ent in greater or lesser abundance in every dietary; but to
what extent they represent an indispensable need of the
animal remains to be learned [20]. The prevailing dogma
in nutrition was that fats were similar in regard to their
nutritional value.
Elmer McCollum (18791967) (fig.4), a former post-
doctoral fellow of Mendel (fig.5), began to study the role
of fats in the diet at the University of Wisconsin. In July
1913, McCollum and his assistant Marguerite Davis
(18871967) reported in The Journal of Biological Chem-
istry that fats were not equal in value for growth in the
rat. Young rats on a diet of casein, lard, lactose, starch,
and salts grew normally if an ether extract from butter or
egg yolk (ether mixed with either butter or egg yolk to
chemically extract substances that were soluble in ether)
was added to the diet. If a similar ether extract of lard or
On the Discovery of Vitamin A
Fig. 4. Elmer McCollum. Fig. 5. Lafayette Mendel.
olive oil was added, the animals died. The investigators
concluded: Our observation that ether extracts from cer-
tain sources improve the condition of animals on such
rations, strongly supports the belief that there are certain
accessory articles in certain food-stuffs which are essen-
tial for normal growth for extended periods [21].
The following month in The Journal of Biological
Chemistry, Osborne and Mendel reported that rats fed a
basal diet of isolated proteins, starch, lard, and protein-
free milk grew normally for about 60 days but then de-
clined and died. The addition of butter or replacement of
lard with butter in the diet allowed normal growth in
young rats. They concluded: In seeking for the essen-
tial accessory factor we have, therefore, been led first to
supply the cream component, in the form of butter it
would seem, therefore, as if a substance exerting a marked
influence upon growth were present in butter [22].
Exaggerated Claims of Discovery by McCollum
In his later writings and autobiography, McCollum
claimed that he discovered vitamin A with his study in
1913, and that this observation was promptly verified by
Osborne and Mendel [23]. McCollums contention to have
discovered vitamin A is based upon his observation that
the unidentified factor was fat soluble. However, Socin
suggested that this unknown substance was fat soluble in
1891 [10] and Stepp showed that it was fat soluble in 1911
[18]. The fat-soluble substance found in butter and egg yolk
in these experiments actually contained three vitamins:
vitamins A, D, and E, which were yet unidentified in 1913.
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Ann Nutr Metab 2012;61:192198 195
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Fig. 6. Paul Karrer. Fig. 7. George Wald.
When Hopkins was awarded a Nobel Prize in 1929 for
the discovery of the vitamins, an editorial in Time mag-
azine (November 11, 1929) groused: Many a US nutri-
tionist declared last week, without carping at the Nobel
award to Professors Hopkins and Eijkman, that, if a fu-
ture Nobel Prize for vitamin research is made, it should
go to Professor Elmer Verner McCollum, 50, head of the
department of chemical hygiene at Johns Hopkins School
of Hygiene & Public Health. In the years that followed,
McCollum often repeated his claim that he had discov-
ered vitamin A. McCollum indeed had a reputation
among vitamin researchers, but it was not all favorable.
When he assumed his new position at Johns Hopkins in
1917, he left the University of Wisconsin under a cloud of
ethical impropriety and academic misconduct [1]. In or-
der to stifle what he perceived as his competitors, includ-
ing the upcoming brilliant scientist Harry Steenbock
(18861953), McCollum stole their research notebooks,
subsequently published their data without their consent
or acknowledgement, violated university policy by pub-
lishing without approval of the station head and dean,
and purposely sabotaged their animal experiments [1]. In
his writings, McCollum continued to attack his rivals
who were working on vitamins, often by giving a delib-
erately distorted or false presentation of their achieve-
ments [1].
Perhaps it is not surprising that no colleague ever
nominated McCollum for a Nobel Prize. The Nobel com-
mittee made it rather clear that this door was closed, since
they stated in retrospect in 1937 that Hopkins had won
the Nobel Prize earlier in 1929 in recognition of his dis-
covery of the vitamins of growth of which one of the
196 Ann Nutr Metab 2012;61:192198
most important has now been identified with vitamin A
[24]. McCollum again claimed that he discovered vita-
mins A in his work A History of Nutrition: The Sequence
of Ideas in Nutrition Investigations (1957). He continued
to snub his colleagues, as he excluded many of the semi-
nal nutrition papers from his book, especially the papers
that were associated with the awarding of a Nobel Prize
[1].
Fat-Soluble A Becomes Vitamin A
In 1914, following the previous line of investigation of
Knapp, Osborne and Mendel showed that rats on a basal
diet developed inflamed eyes and diarrhea, but they re-
covered when cod liver oil or butter fat was added to the
diet [25]. In 1918, McCollum suggested that this acces-
sory food factor that supported growth and eye health be
called fat-soluble A in distinction to water-soluble B,
later known as thiamin [26]. In 1920, Jack Cecil Drum-
mond (18911952), a biochemist at University College,
London, proposed that the nomenclature of the vitamins
be changed: the substances should be spoken of as vita-
min A, B, C, etc. since not all the vitamins were chemical
amines [27]. The same year, Hopkins demonstrated that
vitamin A in cod liver oil could be destroyed by heat and
aeration, and 2 years later McCollum et al. [28] showed
that if cod liver oil was treated with heat and aeration, the
solution could still promote calcium deposition in bones.
The fat-soluble factor that played a role in bone growth
was first called the anti-rachitic factor and then eventu-
ally became known as vitamin D [1].
Further Characterization of Vitamin A
In 1931, the Swiss chemist Paul Karrer (18891971)
(fig. 6) described the chemical structure of vitamin A
[29]. His achievement was recognized with a Nobel Prize
in Chemistry in 1937. Harry Holmes (18791958) and
Ruth Corbet crystallized vitamin A in 1937 at Oberlin
College [30]. In 1946, David Adriaan van Dorp (1915
1995) and Jozef Ferdinand Arens (19142001) synthe-
sized vitamin A [31]. Otto Isler (19201992) et al. [32] at
Hoffmann-La Roche developed a method in 1947 for syn-
thesizing vitamin A that was adaptable for widespread
production. An important piece of the puzzle the role
of vitamin A in vision was solved in the early 1930s
when the biochemist George Wald (19061997) (fig. 7)
described the relationship between vitamin A and
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Semba
University of Edinburgh
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rhodopsin in the visual cycle of the retina [33, 34], a dis-
covery that was acknowledged with a Nobel Prize in
Physiology or Medicine in 1967.
Other major developments in the history of vitamin A,
such as the elucidation of its role in immunity and child
survival, were to come slowly through clinical observa-
tions and clinical trials in the 1930s through the 1990s,
often through a process of repetition and confirmation
[1, 35]. Largely through the work of investigators such as
Alfred Sommer, Keith P. West, Jr., and Gregory Hussey,
and the influential International Vitamin A Consultative
Group, which was active from 1975 to 2006, vitamin A
supplementation became one of the basic measures for
child survival in developing countries [1]. Since the in-
ception of programs for vitamin A supplementation or
fortification of foods, millions of lives of children have
been saved through the efforts of UNICEF, the World
Health Organization, non-governmental organizations,
and governments concerned over the high mortality of
pre-school-aged children in developing countries. Vita-
min A supplementation has been one of the most success-
ful interventions for child survival, along with basic
childhood immunizations, oral rehydration therapy, and
bed nets against malaria [1].
Conclusions
It took about 130 years from the first experiment of
Magendie in 1816 to the synthesis of vitamin A in 1946
and large-scale synthesis in 1947 by Isler at Hoffmann-La
Roche, which made the vitamin available for the preven-
tion and treatment of deficiency. This long, incremental
process began with an initial observation that dogs would
develop corneal ulcers and die if fed sugar and water.
There were subsequent hints that something in milk was
essential for life, and that this substance was fat soluble.
The unknown fat-soluble substance was present in milk,
butter, egg yolk, cod liver oil, and some other foods, and
it was variously known as fat-soluble A, the anti-xeroph-
thalmia vitamin and finally vitamin A. Deduction of the
correct chemical structure of vitamin A, the isolation and
crystallization of vitamin A and its synthesis came in the
1930s and 1940s.

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