A brief history of vitamin C and its deficiency, scurvy

by Harri Hemilä



  1. Scurvy before James Lind
  2. James Lind's treatise 1753
  3. Scurvy as a deficiency of a nutrient
  4. Land scurvy and pediatric scurvy
  5. Animal model for scurvy
  6. Identification and synthesis of vitamin C
  7. Scurvy and the physiological functions of vitamin C
  8. Table 1: Erroneous theories of scurvy by eminent people maintained after James Lind’s controlled trial in 1747, which showed that citrus fruit cured scurvy
  9. References

This text is based on pages 1-3 and 101-4 of Hemilä (2006).
This document has up to date links
to documents that are available via the net.
A few old and difficult to reach documents,
such as Funk's (1912) paper introducing the term "vitamine"
have been digitalized so that they can be read as original texts.
Harri Hemilä
Department of Public Health
University of Helsinki,  Helsinki, Finland
harri.hemila@helsinki.fi
Home:  http://www.mv.helsinki.fi/home/hemila

This file:  http://www.mv.helsinki.fi/home/hemila/history

Version May 29, 2012

We were all hearty seamen, no cold did we fear
And we have from all sickness entirely kept clear
Thanks be to the Captain he has proved so good
Amongst all the Islands to give us fresh food.

Song of James Cook’s Sailors
(Kodicek & Young 1969)



Scurvy before James Lind

Scurvy, vitamin C deficiency, was a serious occupational disease of sailors in the Age of Sail. It has been estimated that over two million sailors perished from scurvy (Carpenter 1986; Harvie 2002; Bown 2003).

Vasco da Gama began his expedition to India in 1497 and when his ships arrived on southeast coast of Africa, most of the crew were afflicted with scurvy. Da Gama recorded that "Many of our men fell ill here, their feet and hands swelling, and their gums growing over their teeth so that they could not eat." As they sailed farther up the east coast of Africa, they met local traders, who traded them fresh oranges, and within 6 days of eating them, the crew recovered. Although da Gama recorded that "It pleased God in his mercy that ... all our sick recovered their health for the air of this place is very good," the crew were convinced that the oranges that they had eaten were powerful curatives, because they particularly asked for them the next time scurvy appeared (Carpenter 1986 pp 1-3). It is thought that scurvy was the cause of the deaths of 100 of Vasco da Gamas 160 men (Harvie 2002 pp 12).

The English sea captain Sir Richard Hawkins stated in 1622 that "In 20 years, since that I have used the sea, I dare take upon me to give accompt of 10,000 men consumed with scurvy" emphasizing the magnitude of the problem. Hawkins "wished that some learned man would write of it, for it is the plague of the sea, and the spoil of mariners." In the 1780s, twenty-one British warships were stationed in the West Indies, which had become the major theatre for naval battles involving France, Spain, and England during the War of American Independence. Sir Gilbert Blane, who was the personal physician to the admiral, counted that, during his first year in the West Indies, out of 12,019 mariners only 60 died from enemy action, whereas 1,518 perished from disease, with cases of scurvy outnumbering all other illnesses combined (Bown 2003 pp 199-225; Carpenter 1986 pp 91-7), corresponding to a mortality rate for scurvy of about 1 per 10 person-years.

When Commodore George Anson set out with 8 ships and 1,854 sailors to the South Seas in 1740, he returned in 1744 with only 1 ship and 188 men; the great majority of the rest died of scurvy (Gordon 1984; Carpenter 1986 pp 46-51; Watt 1998). In contrast, during James Cook’s second voyage towards the South Pole and round the World, from 1772 to 1775, he lost no men to scurvy: "… the Resolution performed a voyage of three years and eighteen days, through all climates … with the loss of one man only by disease, and who died of a complicated and lingering illness, without any mixture of scurvy. Two others were unfortunately drowned, and one killed by a fall; so that of the whole number with which I set out from England I lost only four" (Cook 1776). After this voyage, Cook was honored with the Copley Medal of the Royal Society, Cook’s most prestigious award. This was not for his navigational discoveries, but for his success in maintaining a long sea voyage without a death from scurvy among the men in his crew (Chick 1953; Kodicek & Young 1969). Still, Cook could not receive the medal in person because he had already left on yet another voyage, in which he was to be killed by natives on a beach in Hawaii.

Paradoxically, Cook’s success in preventing scurvy, far from hastening the cure of the disease, instead delayed the identification of the actual cure (Lloyd 1961). Cook was primarily a navigator and explorer and not a dietician, and he did not examine specifically which of the numerous antiscurvy measures was the actual reason for its absence. Cook’s experience could thus not be used to exclude useless treatments, and false explanations for the cause and treatment of scurvy prevailed for a long period in spite of his success in keeping his own sailors free of it (Table 1).

Strong observational evidence had shown that fruit had been useful for treating and preventing scurvy since Vasco da Gama’s voyage, and Hawkins (1622) commented that "That which I have seene most fruitfull for this sicknesse, is sower oranges and lemmons." The benefit of fruit was, however, forgotten for a long period and was rediscovered only in the 1700s.

James Lind's treatise 1753

James Lind (1753) carried out a systematic review of all the earlier literature on scurvy and wrote the classic monograph A Treatise of the Scurvy. At the end of his treatise, Lind wrote a brief summary of each of the earlier publications on scurvy ("Bibliotheca scorbutica"; Lind 1753 pp 249-354). In the literature before Lind, the clinical definition of scurvy had become highly ambiguous and, for example, one of the earlier authors had stated "As this case cannot properly be referred to any other disease, it may justly be deemed scorbutic" (p 36). Because of the imprecise definitions of scurvy, and in many cases using the name for unrelated diseases as we define it nowadays, Lind discarded most of the earlier texts by eminent authors. Working for years as a surgeon on Navy ships, Lind had substantial personal experience with scorbutic patients, and his own clinical definition was based on "putrid gums, swelled legs, and spots, accompanying each other, and in their progress usually attended with rigid tendons in the ham, are observed in no other distemper" (p 53). In contrast to most earlier authors on scurvy, Lind’s line of exploring the nature of the disease was empirical: "I shall propose nothing dictated merely from theory; but shall confirm all by experience and facts, the surest and most unerring guides" (p 144).

In 1747, Lind carried out the first well described controlled trial in medicine, on HMS Salisbury (1753 pp 145-8). In this trial, Lind kept "12 patients in the scurvy … their cases were as similar as I could have them," in the same quarters; and he saw to it that they all had the same diet. Groups of 2 men were then allocated to 6 different daily treatments for a period of 14 days. One group was administered 2 oranges and 1 lemon per day for 6 days only, when the supply was exhausted. Other groups were administered vinegar, sea-water, and other supposed anti-scurvy remedies. From this trial, Lind concluded that "The most sudden and visible good effects were perceived from the use of the oranges and lemons; one of those who had taken them, being at the end of six days fit for duty" (p 146).

Lind’s trial was a milestone in medical research methodology (Dudley 1953; Thomas 1969, 1997; Hughes 1975; McBride 1991; Dunn 1997; Friedman et al. 1998 p 1; Manchester 1998a; Sutton 2003; Currie 2003; Milne & Chalmers 2004). Hampton (2002) stated that "The elegant trial of the use of oranges and lemons for the treatment of scurvy was hardly bettered until the trial of streptomycin for tuberculosis designed by Austin Bradford Hill [in 1948]."

Thus, Lind’s trial provided further empirical evidence that citrus fruits could cure scurvy. However, most current authors refer to this trial out of context, claiming that it proved the essential role of fruit in preventing scurvy, and establishing a way to understand deficiency diseases (Carpenter 1986; Bartholomew 2002a, 2002b). The trial is described in just 3 pages of a book of some 350 pages. Lind himself did not put as much weight on his trial as the current commentators retrospectively do (see Table). In fact, he drew his own conclusions, which were completely false, about the etiology of scurvy from observational data.

Lind was convinced that lack of fruit and vegetables was not the primary etiological cause of scurvy, and argued at length for this conclusion. "Before determining what are the true causes of scurvy being so often epidemic at sea, it may not be amiss to remark what they are not, although commonly accused" (1753 p 71). "Others have supposed such to be the constitution of the human body, that health and life cannot be preserved long, without the use of green herbage, vegetables, and fruits; and that a long abstinence from these, is alone the cause of scurvy. But if this were truly the case, we must have had the scurvy very accurately described by the ancients; whose chief study seems to have been the art of war; and whose manner of besieging towns was generally by a blockage, till they had forced a surrender by famine. Now, as they held out many months, sometimes years, without a supply of vegetables; we should, no doubt, have heard of many dying of the scurvy" (pp 73-4). "There are persons everywhere, who, from choice, eat few or no green vegetables; and some countries are deprived of the use of them for five or six months of the year; as is the case of many parts in the highlands of Scotland, Newfoundland, etc., where, however, the scurvy is not a usual malady" (p 74). Lind also describes his own experience while on board HMS Salisbury where he did not observe a correlation between the consumption of greens and the occurrence of scurvy, concluding that "although it is a certain and experienced truth, that the use of greens and vegetables is effectual in preventing the disease, and extremely beneficial in the cure … yet there are unquestionably to be found at sea, other strong sources of [scurvy]; which we shall hereafter distinguish by the name of the predisposing causes to it." (p 76; Lind’s italics).

Thereafter Lind extensively describes his own notions of the etiology of scurvy concluding that "I am certain it will be allowed, by all who have had an opportunity of making observations on this disease at sea, or will attentively consider the situation of seamen there, that the principal
and main predisposing cause to it, is a manifest and obvious quality of the air, viz. its moisture" (pp 84-5; Lind’s italics; Martini 2004). Lind also argued "I will venture to affirm, that, without any one exception, scurvy is unknown in dry places" (p 98), "The lazy and indolent, and those of a sedentary life … are most subject to scurvy; while hard labourers … keep entirely free. … Those that are of a cheerful and contented disposition, are less liable to it, than others of a discontented and melancholy mind" (p 105). Finally, when discussing "the cure of the disease, and its symptoms" in the latter part of his treatise, Lind stated "All mankind have not the benefit of a pure wholesome air, warm dry lodgings, with proper conveniences to guard against the inclemency of different weather and seasons… Experience shews, that the cure of the adventitious scurvy is very simple, viz. a pure dry air, with the use of green herbage or wholesome vegetables, almost of any sort; which for the most part prove effectual… Thus a free and pure countryair, with such moderate exercise as at the same time conduces to the agreeable amusement of the mind, is requisite" (pp 178-9). "And by all faithful and accurate observations made on this disease, moisture is experienced to be the principal and main predisposing cause to it" (p 206). Although proposing ‘moisture’ explicitly as the principal cause of scurvy, Lind did consider that diet may have importance as an ‘occasional cause’ of scurvy, i.e., secondary to moisture.

Scurvy as a deficiency of a nutrient

The correct explanation of the etiology of scurvy was proposed in 1734, i.e., before Lind’s trial and monograph, by John Bachstrom, a physician in Holland who claimed that the cause of scurvy was the absence of fresh vegetable food from the diet for a considerable time (Carpenter 1986 pp 44-5; Lind 1753 pp 314-7). Carpenter comments that "Bachstrom’s treatise seems to the modern reader a straightforward argument and one that deserved at least a serious consideration. But to the contemporary main-line physician it was not impressive because it dealt with a single disease in isolation and did nothing toward establishing a view of the nature of ‘disease’ in general – an ideal which the medical profession had as its goals, by analogy with the universal laws being developed by the physicists at that time. In other words, Bachstrom was ‘a mere empirick’." Lind explicitly disagreed with Bachstrom’s proposal that "a long abstinence from fruits and vegetables is alone the cause of scurvy" (1753 p 73).

One hundred years later, John Elliotson (1831), professor of medicine in London, proposed specifically that "scurvy is disease purely chemical. The body, structure, and functions are not in the least in fault; in one sense, each part of the system is ready to perform all its functions, but one of the external things necessary for its doing so is taken away. In the case of suffocation, the body is not at all in fault, but it suffers from a want of fresh air; so in scurvy, the functions are all right, but the food which the body by nature requires is withheld from it… The case of scurvy is exactly like the case of impending suffocation – the body would be in good health if not deprived of its proper external supply." A few years later, in 1842, George Budd also suggested that scurvy was a deficiency disease: "From this we must infer, that the ill effects of a diet consisting of sugar, starch, oil, fat, do not result from want of protein only but from want of other principles also requisite for the support of the body. Perhaps the deficiency of each principle shows itself in a particular way" (Hughes 1973; Carter 1977; Carpenter 1986 pp 98-9, 249-51; Cook 2004). These were visionary considerations far ahead of their time.

The concept of necessary minor constituents started to be accepted in main-line medicine over half a century after Elliotson and Budd published their arguments, in the early twentieth century. In 1906, Sir Frederick Hopkins wrote that "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. Physiological evolution, I believe, has made some of these well-nigh as essential as are the basal constituents of diet… The field is almost unexplored; only is it certain that there are many minor factors in all diets of which the body takes account. In diseases such as rickets, and particularly in scurvy, we have had for long years knowledge of a dietetic factor; but though we know how to benefit these conditions empirically, the real errors in the diet are to this day quite obscure. They are, however, certainly of the kind which comprises these minimal qualitative factors that I am considering." Hopkins was awarded the 1929 Nobel Prize in Medicine or Physiology for his discovery of the growth-stimulating vitamins, which he called ‘accessory food factors’ and in 1931 he became the president of the Royal Society (Hopkins 1906, 1912, 1912, 1929; Harris 1947a, 1947b; Needham 1962a,b; Kamminga 1997; Carpenter 2003b, 2004; NF 2007a).

In 1912, Casimir Funk assembled all the various strands of work supporting the deficiency theory of disease, concluding that "The diseases mentioned above [in the title of the paper] present certain general characters which justify their inclusion in one group, called deficiency diseases. They were considered for years either as intoxications by food or as infectious diseases, and twenty years of experimental work were necessary to show that diseases occur which are caused by a deficiency of some essential substances in the food. Although this view is not yet generally accepted, there is now sufficient evidence to convince everybody of its truth, if the trouble be taken to follow step by step the development of our knowledge on this subject. This article is written with the intention of giving a summary of the modern investigations … there is perhaps no other subject in medicine where so many contradictory and inexact statements were made, which instead of advancing the research retarded it by leading investigators in a wrong direction." Subsequent research confirmed most of Funk’s opinions and vindicated most of the arguments he provided in their support. Since his paper, additional work on the deficiency diseases can be thought of as elaboration of an existing theory (Carter 1977); however, see footnote to Table 1. Funk (1912) also coined the term ‘vitamine’ (‘vital’ substances that were chemically ‘amines’), but the letter ‘e’ was later dropped out when it was found that not all these vital substances were ‘amines’, so that the term for later use became ‘vitamin’ (Drummond 1920; Rosenfeld 1997; Carpenter 2004).

Nevertheless, as to the actual cure of scurvy, it took several decades after Lind’s trial in 1747 before citrus fruits were properly utilized in preventing it. Sir John Pringle believed that scurvy was caused by putrefaction, his own theory being that ‘wort of malt’ was its cure and, because Sir John happened to be the president of the Royal Society, ‘wort of malt’ was a more respectable remedy for scurvy than lemons long after Lind’s controlled trial (Table 1). In 1778, Pringle resigned his position at the Royal Society, and in 1795, Sir Gilbert Blane, a follower of Lind, was able to persuade the British Admiralty to issue a daily ration of lemon juice to all sailors, which virtually eliminated scurvy aboard Navy ships. It seems this defeat of vitamin C deficiency was a major reason why the British Navy was able to protect the country against Napoleon’s invasion and, in particular, why Nelson was able to beat the French and Spanish fleets at the Battle of Trafalgar in 1805 when their mariners were suffering from scurvy. Never before, and never since, has vitamin C as a chemical substance had such a crucial role in global politics (Bown 2003 pp 227-55).

Land scurvy and pediatric scurvy

Although scurvy caused its greatest evils on the long sea voyages, it has also been a problem on land, sometimes called the ‘land scurvy’ (Lind 1753 pp 52-63; Hess 1920 pp 1-22; Lorenz 1953, 1957; Wilson 1975; Carpenter 1986 pp 98-132; Hughes 1990; Bollet 1992; Harvie 2002 pp 225-34). French explorer Jacques Cartier had winter on the Saint Lawrence River in 1535-6 since his ships were frozen in the ice, and most of his crew got scurvy. Local indians taught them to prepare juice of white cedar and "after drinking it two or three times, they recovered health and strength and were cured of all the diseases they had ever had" (Carpenter 1986 pp 7-12; Martini 2002). Juice made of pine needles was used also during the siege of Leningrad in the Second World War to prevent scurvy (Shishkin 1943). Land scurvy has been a problem in various circumstances. In the American Civil War of 1861-1865, 7,000 Union army deaths were directly attributed to scurvy, and another 45,000 deaths from dysentery and diarrhea followed from severe scurvy. In the California Gold Rush, some 10,000 men died from scurvy, half of them succumbing in the first two winters alone. In the Irish Famine, caused by the failure of the potato crops in the late 1840s, approximately one million people died of scurvy and other diseases.

In the late 1800s, scurvy became a pediatric problem when children were administered heated milk and artificial foods which did not contain vitamin C; this form of scurvy was called ‘the Barlow’s disease’ (Barlow 1894; Hess & Fish 1914; Aspin 1993; Rajakumar 2001; Carpenter 1986 pp 158-72, 2003a). In Scandinavia, ‘land scurvy’ was explicitly described in the 1500s, being largely associated with wars (Olaus Magnus Gothus 1555). Nowadays, ‘land scurvy’ is a problem in the refugee camps, where its prevalence has been up to 44% at the upper extreme (in Somalia in 1985; WHO 1999), and in Afghanistan (Ahmad 2002). In the developed world, severe vitamin C deficiency is currently rare; nevertheless, because its clinical features are no longer familiar, even frank scurvy may remain undiagnosed (Sherlock & Rothschild 1967; Reuler et al. 1985; Scully et al. 1986; Fain et al. 1998; Hirschmann & Raugi 1999; Weinstein et al. 2001; Akikusa et al. 2003; Bingham et al. 2003; DeLuna 2003; Pimentel 2003).

Animal model for scurvy

Although there was strong observational evidence even before Lind’s trial that citrus fruits were beneficial for scurvy, there was no biological rationalization for fruit, and a large number of false theories about scurvy prevailed long after Lind’s controlled trial (Table 1). Since vitamin C is synthesized by all mammals with the few exceptions of primates, the guinea pig and fruit-eating bats, a reasonable animal model for scurvy was not easy to find. Holst and Frölich (1907; Johnson 1954) were able to produce scurvy in guinea pigs by administering them a diet deficient in fruit, whereby a suitable animal model for vitamin C deficiency was identified. Since then, the guinea pig has been the most important animal model for studies examining the physiological effects of vitamin C. Carpenter (1986 p 173, 2003a) considered that the Holst and Frölich paper has been the most important in the whole history of vitamin C and scurvy; however, see footnote to Table 1.

Identification and synthesis of vitamin C

There were a few systematic efforts to isolate vitamin C, but it was first isolated by chance by Albert Szent-Györgyi (1933, 1963, 1971; Bendiner 1982; Hughes 1983; Edsall 1986; Straub 1987; Grazer 1988; NLM 2007b), who had initially considered that "Vitamins were, to my mind, theoretically uninteresting. ‘Vitamin’ means that one has to eat it. What one has to eat is the first concern of the chef, not the scientist." Nevertheless, in 1928, while working in Frederick Hopkin’s laboratory, Szent-Györgyi isolated a sugar-like molecule from adrenals and citrus fruits. Since he did not know much about the substance, he proposed the name ‘ignose’ (‘ignorant’ plus ‘-ose’ which is the suffix for sugar), but the editor of the Biochemical Journal did not like jokes and rejected the name. Thereafter Szent-Györgyi proposed ‘Godnose’ (‘God knows’ the purpose of the substance), but the fate of this second proposal was the same, and the substance was finally named ‘hexuronic acid’ since it has 6 carbon atoms and is acidic. In 1932, when Szent-Györgyi showed that the substance cured scurvy in guinea pigs, the substance was renamed ‘ascorbic acid’ (‘scorbutus’ is scurvy in Latin). Szent-Györgyi spent the next several years "preaching vitamin C" (as he put it) all over Europe, suggesting that it might be valuable as a preventive or cure for the common cold and other illnesses. He attempted to interest some of the British biochemists in running some clinical trials, but they considered the idea crankish and refused to consider it. Vitamin C proved disappointing as a miracle cure, however, and Szent- Györgyi eventually got back to his basic research in other areas (NLM 2007b). The Nobel Prize in Medicine or Physiology was awarded to Szent-Györgyi in 1937 for identifying vitamin C and for studies on energy metabolism (Szent-Györgyi 1937; Krebs 1970; Manchester 1998b; NF 2007b). In parallel with Szent-Györgyi’s work, Charles King identified vitamin C at nearly the same time and this led to disagreements over who was first (King 1953, 1968, 1979; Szent-Györgyi 1938; Jukes 1988; Stare & Stare 1988; NLM 2007c).

The chemical structure of vitamin C was solved by Sir Norman Haworth, who was awarded the Nobel Prize in Chemistry in 1937 (NF 2007c). In parallel with Haworth’s vitamin C synthesis, Tadeus Reichstein developed a more practical method of synthesizing vitamin C, which became commercially useful, and patents allowed Reichstein to amass considerable financial rewards. Although many people were surprised that Reichstein did not receive the Nobel Prize for the synthesis of vitamin C, he received the Nobel Prize in Medicine or Physiology in 1951 for isolating and identifying cortisone (Rothschild 1999; NF 2007d). The Reichstein synthesis of vitamin C has been used to produce it for decades, but currently there is a change to synthetic processes involving genetically modified microbes. The current world production of vitamin C is about 100,000,000 kg per year,  i.e., 15 grams per year per each inhabitant of the globe (Hancock & Viola 2002). Approximately half of the vitamin C produced is used in vitamin supplements and pharmaceutical preparations. A survey of female physicians in the USA found that 18% of them were regularly using vitamin C supplements (Frank et al. 2000), and about 30% of the general US adult population takes vitamin C supplements (FNB 2000). This high level consumption of vitamin C by people’s own initiative makes the health effects of supplementation of considerable public health interest, be they positive or negative. .
 

Scurvy and the physiological functions of vitamin C


Typical symptoms of classical scurvy include swollen and bleeding gums, dropping teeth, and poor healing of wounds (Wolbach & Howe 1926; Hess 1920; Crandon et al. 1940; Peters et al. 1948; Krebs 1953; Hodges et al. 1971; Carpenter 1986; Harvie 2002; Bown 2003). Since these symptoms are explained by the participation of vitamin C in the synthesis of collagen, major textbooks of biochemistry mention only the role of vitamin C in proline hydroxylation (e.g., Berg et al. 2002). Vitamin C, however, also participates in the enzymatic synthesis of dopamine, carnitine, and a number of neuroendocrine peptides (Englard & Seifter 1986; Levine 1986; Hughes 1988; Padh 1990; Rebouche 1991; Rice 2000). In addition, vitamin C participates in the transformation of cholesterol into bile acids (Ginter 1973, 1978; Hemilä 1992c). The survival time of vitamin C deficient guinea pigs is extended by carnitine (Jones & Hughes 1982) and glutathione (Mårtensson et al. 1993), indicating that scurvy is not explained simply by the defects in collagen hydroxylation. Furthermore, vitamin C is a powerful reducing agent, antioxidant, and reacts with oxidants produced by phagocytes, through which it may affect the functions of the immune system (Hemilä 1992a, 2006). Thus the notion presented in the textbooks that vitamin C participates only in the hydroxylation of proline in collagen is grossly oversimplified and misleading.

A number of early animal studies indicated that vitamin C may affect susceptibility to infection (Robertsson 1934; Perla & Marmorston 1937a    1937b; see Animal infections). After James Lind’s treatise on scurvy, the next English treatise was written by Alfred Hess (1920; Darby & Woodruff 1962; Wiedemann 1993), a pediatrician in New York. In various parts of his monograph, Hess noted the increased risk of infection, in particular pneumonia, in vitamin C deficiency. A decade later, in a major medical journal, Hess (1932) commented that in “infantile scurvy … a lack of the antiscorbutic factor which leads to scurvy, at the same time predisposes to infections [particularly of the respiratory tract]. … Similar susceptibility to infections goes hand in hand with adult scurvy.” Such opinions did not leave traces in mainstream medicine and, according to the current widespread consensus, vitamin C has relevance only in preventing and curing classical scurvy.


Table 1: Erroneous theories of scurvy by eminent people maintained after James Lind’s controlled trial in 1747, which showed that citrus fruit cured scurvy

Person

His position

Theory of scurvy

James Lind (1716-1794)

Carried out the first systematic review and the first well documented controlled trial

Caused by moisture, prevented and cured by dry air

 

Sir John Pringle (1707-1787)

President of the Royal Society, Physician to King George III

Caused by putrefaction, 
correctable by foods fermenting to yield carbon dioxide (wort of malt)

Sir Robert Christison (1797-1882)

President of the British Medical Association, Physician to Queen Victoria

Caused by protein deficiency

Lord Lister (1827-1912)

President of the Royal Society, Surgeon to Queen Victoria

Caused by ptomaine intoxication (substances in spoiled food)

Jean-Antoine Vilemin (1827-1892)

Member of the Academy of Medicine, Paris

Caused by a contagious miasm

William Hammond (1828-1900)

US Army Surgeon-General

Caused by deficiency of potassium and/or iron

Elmer McCollum (1879-1967) *

The most important US nutrition scientist in the early 1900s

Caused by constipation and cured by laxatives


Modified of Carpenter (1986) Table 10.4.

* McCollum discovered vitamin A and was “one of the giants of nutritional biochemistry” (Simoni et al. 2002). For the work of McCollum, see McCollum (1953, 1967  1967extracts), Rider (1970), Day (1974, 1979, 1997), Schneider (1986), Carpenter (2003b), JHBSPH (2007).

Each year the E.V. McCollum Award is given by the American Society of Clinical Nutrition to a clinical investigator currently perceived as a major creative force, actively generating new concepts in nutrition, and personally seeing to the execution of studies testing the validity of these concepts (ASCN 2005). In 1972, the McCollum award was given to Victor Herbert (see pp 62-66 of Hemilä 2006 and Hemilä 1994b), and in 1990 to Ranjit K. Chandra (see  Smith 2005).

In 1917, McCollum and Pitz published the results of a series of experiments with guinea pigs in a paper which was categorized as a “classic paper” by the Journal of Biological Chemistry (Simoni et al. 2002).

McCollum and Pitz (1917) stated in the Journal of Biological Chemistry paper that “the experimental data presented in this paper form a conclusive line of evidence which proves that scurvy in the guinea pig is not a deficiency disease in the sense in which Holst, Funk, Hess and others have regarded it … The efficiency of orange juice as an antiscorbutic may well be accounted for by its content of sodium and potassium citrates, both of which possess laxative properties” (p 234), “chart 7 offers definite and convincing evidence that scurvy is in reality the sequel to retention of feces in the cecum” (p 235), “we are inclined to attribute the beneficial effects of orange juice to its laxative action” (p 237), “the observations reported in this paper furnish definite support for the idea that scurvy in the guinea pig is not the result of the deficiency of a specific protective substance… it becomes necessary to offer a new interpretation as to the etiology of experimental scurvy in the guinea pig. Our interpretation, that the first cause of the disease is associated with the retention of feces … is we believe supported by adequate experimental data” (pp 238-9). “The significance of this interpretation is far reaching. It removes from the list one of the syndromes (scurvy) which has long been generally accepted as being due to dietary deficiency” (p 239). “This fact, together with convincing evidence that scurvy is not in reality a deficiency disease in the sense of being caused by a lack of specific protective substance, warrants an attitude of scepticism regarding the validity of the “vitamine” theory of the etiology of such other diseases as pellagra, rickets, etc., which have been attributed to specific dietary deficiency” (p 239-40).  "… There is therefore no reason whatever why we should assume as Voegtlin, Goldberger, Funk, and other have done that pellagra is due to a lack of a specific unidentified dietary factor, a “vitamine”" (p 241).

McCollum (1917) repeated his conclusions in JAMA: “Scurvy in the guinea-pig is the result of the retention of feces… I am inclined to attribute the protective power of orange juice as an antiscorbutic to its content of certain salts of citric acid, rather than to the presence of an unidentified organic substance of the class of the so-called vitamins” (p 1385).  McCollum repeated these conclusion in JAMA also in 1918.


References

NOTE: all the links in the main text should be freely accessible, but several of the links below require a permission from publisher.


Ahmad K (2002) Scurvy outbreak in Afghanistan prompts food aid concerns [news]. Lancet 359:1044 

Akikusa JD, Garrick D, Nash MC (2003) Scurvy: forgotten but not gone. J Paediatr Child Health 39:75-7 

ASCN [American Society for Clinical Nutrition] (2005) The E.V. McCollum Award   *  McCollum 

Aspin RK (1993) The papers of sir Thomas Barlow, BT, KCVO, FRS, PRCP (1845-1945). Med Hist 37:333-40  
    * also BMJ (1983);287:1862-3

Barlow T (1894) Infantile scurvy and its relation to rickets: the Bradshaw lecture. Lancet 144:1075-80

Bartholomew M (2002a) James Lind’s Treatise of the Scurvy (1753). Postgrad Med J 78:695-6

Bartholomew M (2002b) James Lind and scurvy: a revaluation. J Maritime Res (1 Jan)      Journal Home 

Bendiner E (1982) Albert Szent-Györgyi: the art of being wrong. Hosp Pract 17(5):179-92

Berg JM, Tymoczko JL, Stryer L (2002) Biochemistry, 5th edn. NY: Freeman. pp 217-9

Bingham AC, Kimura Y, Imundo L (2003) A 16-year-old boy with purpura and leg pain. J Pediatr 142:560-3 

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Bown SR (2003) Scurvy: How a Surgeon, a Mariner and a Gentleman Solved the Greatest Medical Mystery of the Age of Sail. Chichester, West Sussex, UK: Summersdale 
* Book reviews J Clin Invest (2004);114:1690   Nat Hist (2004);(Mar) 

Carpenter KJ (1986) The History of Scurvy and Vitamin C. Cambridge, UK: Cambridge University Press  
* Book reviews Nature (1986);324:177   J Hist Med Allied Sci (1987);42:386-7   Med Hist (1987);31:231-2   Yale J Biol Med (1989);62(3):333–334  CMAJ (1986)135(10):1160


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Carpenter KJ (2003b) A short history of nutritional science: Part 3 (1912-1944). J Nutr 133:3023-32 

Carpenter KJ (2004) The Nobel Prize and the discovery of vitamins. 

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Drummond JC (1920) The nomenclature of the so-called accessory food factors (vitamins). Biochem J 14:660  
  * also Nutr Rev (1974) 32:209

Dudley S (1953) James Lind: laudatory address. Proc Nutr Soc 12:202-9 

Dunn PM (1997) James Lind (1716-94) of Edinburgh and the treatment of scurvy. Arch Dis Childhood 76:F64-5  * also Arch Dis Childhood 1997

Edsall JT (1986) Albert Szent-Györgi (1893-1986). Nature 324:409 

Elliotson (1831) Clinical lectures. Lancet 15:649-56    CH   BM

Englard S, Seifter S (1986) The biochemical functions of ascorbic acid. Annu Rev Nutr 6:365-406 

Fain O, Mathieu E, Thomas M (1998) Scurvy in patients with cancer. BMJ 316:1661-2 

FNB [Food and Nutrition Board, Institute of Medicine] (2000) Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids. Washington DC: National Academy Press vitamin C pp 95-185 Vitamin C

Frank E, Bendich A, Dennison M (2000) Use of vitamin-mineral supplements by female physicians in the United States. Am J Clin Nutr 72:969-75

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          * excerpts Nutr Rev (1975);33:176-7 

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Harvie DI (2002) Limeys: the True Story of One Man’s War against Ignorance, the Establishment and the Deadly Scurvy. Stroud, Gloucestershire, UK: Sutton 
     * Book reviews  BMJ (2002);325:841   J Mil Hist (2003);67:557-8    Bull Hist Med (2004);78:717-9  

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 * excerpts Nutr Rev (1986);44:370-1 

Hemilä H (1992a) Vitamin C and the Common Cold.  Br J Nutr 67:3-16    Manu with links to Refs   CH 

Hemilä H (1992c) Vitamin C and plasma cholesterol. Crit Rev Food Sci Nutr 32:33-57

Hemilä H (1994b) The good and harm of vitamin C [Letter]. Nutrition Today Nr.2;(April):49-50  Manu with links to Refs

Hemilä H (2006) Do vitamins C and E affect respiratory infections? [Dissertation]. University of Helsinki, Finland   Other address Hemilä 2006

Hess AF (1914) Infantile scurvy: the blood, the blood vessels and the diet. Am J Dis Children 8:399-405
   * see Nutr Rev (1977) 35:12-4

Hess AF (1920) Scurvy: Past and Present. Philadelphia, PA: Lippincott - a digitalized version is available at The Cornell University Library  
     *    Book review  Am J Public Health

Hess AF (1932) Diet, nutrition and infection. N Engl J Med 207:637-48    BM  
   * also:  Hess AF (1917) Infantile scurvy. Part V. Am J Dis Child 14:337-53

Hirschmann JV, Raugi GJ (1999) Adult scurvy. J Am Acad Dermatol 41:895-906

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Holst A, Frölich T (1907) Experimental studies relating to ship-beri-beri and scurvy. Part II. On the etiology of scurvy. J Hyg (Lond) 7:634-71 * excerpts Nutr Rev (1974);32:273-5 

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Hopkins F (1929) The earlier history of vitamin research. Nobel Lecture.  

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King CG (1968) Fifty years of experience in nutrition and a look to the future.  PMC  CH  


King CG (1979) The isolation of vitamin C from lemon juice. Fed Proc 38:2681-3   
  ***  See also: major papers on vitamin C by King and biographies

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Lind J (1753) A Treatise of the Scurvy, in Three Parts, Containing an Inquiry into the Nature, Causes, and Cure of That Disease. Together with a Critical and Chronological View of What Has Been Published on the Subject. Edinburgh: Sands, Murray and Cochran. 456 pp. 

Republished in: (1953) Lind’s Treatise on Scurvy [Stewart CP, Gutrie D, eds]. Edinburgh, UK: Edinburgh University Press [pages in the current text refer to the 1953 reprint] 

*see excerpts: Nutr Rev (1984);41:155-7 * also James Lind Library (JLL)    JLL 1    JLL 2    JLL 3    Bull WHO (2004);82:793-6  

Lloyd CC (1963) The conquest of scurvy. Br J History of Science 1:357-363

Lloyd C (1961) The introduction of lemon juice as a cure for scurvy. Bull Hist Med 35:123-32

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Lorenz AJ (1957) Scurvy in the Gold Rush. J Hist Med Allied Sci 12:473-510 

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Martini E (2002) Jacques Cartier witnesses a treatment for scurvy. Vesalius 8(1):2-6   * also  Cartier 1   Cartier 2   Cartier 3 

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McCollum EV (1953) My early experiences in the study of foods and nutrition. Annu Rev Biochem 22:1-16 

McCollum EV (1967) The paths to the discovery of vitamins A and D. J Nutr 91:11-6 
 * see Nutr Rev (1986) 44:242-4

McCollum EV, Pitz W (1917) The “vitamine” hypothesis and deficiency diseases: a study of experimental scurvy. J Biol Chem 31:229-53 
    * This is a “Classic article” of the Journal of Biological Chemistry, see Simoni et al. (2002) 

Milne I, Chalmers I (2004) Documenting the evidence: the case of scurvy. Bull WHO 82:791-2 * also Bull WHO (2004);82:793-6 

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NF [Nobel Foundation] (2005a) Sir Frederick Hopkins – Biography

NF [Nobel Foundation] (2005b) Albert Szent-Györgyi – Biography

NF [Nobel Foundation] (2005c) Norman Haworth – Biography

NF [Nobel Foundation] (2005d) Tadeus Reichstein – Biography

NLM [National Library of Medicine] (2005b) The Albert Szent-Gyorgyi Papers. Profiles in Science    Summary in Science

NLM [National Library of Medicine] (2005c) Finding Aid to the Charles Glen King Papers, 1918-1988 

Olaus Magnus Gothus (1555) Historia de Gentibus Septentrionalibus. Roma. Finnish translations: (2002) Suomalaiset Pohjoisten Kansojen Historiassa, osa 2. Jyväskylä: Gummerus p 407; and (1977) Pohjoisten Kansojen Historia, Suomea Koskevat Kuvaukset. Helsinki: Otava. pp 131-2 

Padh H (1990) Cellular functions of ascorbic acid. Biochem Cell Biol 68:1166-73

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  *  See also: major papers on vitamin C by Szent-Györgyi and biographies

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**************

Other  historical references available via the net.
Not included in the text.

James Lind's legacy to clinical medicine.
S M Mellinkoff
West J Med. 1995 April; 162(4): 367–369.
PMCID: PMC1022783

Scurvy resulting from a self-imposed diet.
J F Walter
West J Med. 1979 February; 130(2): 177–179.
PMCID: PMC1238551

The Prevention of Scurvy in the Navy
J. L. Priston
Proc R Soc Med. 1926; 19(War Sect): 7–14.
PMCID: PMC1948172



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© 2006-2008 Harri Hemilä. This text is an open-access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  


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Based on a work at www.mv.helsinki.fi/home/hemila/history.


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