Chesney, Russell W.
Rickets was a scourge of children living in northern climes in the postindustrial age (1). The story of solving the puzzle of its cause, pathogenesis, cure, and prevention is one of the great sagas in the history of nutrition and a great accomplishment in 20th-century medicine (2). The importance of animal models of rickets in establishing the role of a deficient nutrient is both clear and murky. In one sense, it represented serendipity. Sometimes it showed brilliant insights on the part of the investigator. From the perspective of today, a better understanding of the role of 6 early animal models and what they contributed to solving the puzzle emerges.
Rickets was a common disorder of infants living in the urban areas of the United Kingdom, northern Europe, the northern latitudes of Japan and China, and North America. First appearing around 1650, it was well described by Glisson and Whistler (3,4). Termed the “English disease” (4), rickets had a prevalence rate of 60% or more. Children growing up in Glasgow, Birmingham, Manchester, and London in the United Kingdom developed rickets at rates far greater than those living in rural areas, and it was more common during the winter months (5). In an autopsy series of infant deaths performed by Schmorl in Dresden, Germany (6), which is at a latitude similar to the United Kingdom, >90% of the subjects had bone growth plate and histologic findings consistent with rickets. In an American series published later, >60% of infant autopsies in Baltimore showed rachitic changes (7). This prevalence indicated that rickets was a major health issue in the late 19th and early 20th centuries (1,2,8).
Rickets is a condition of the bones of growing children, expressed as a widening of the ends of bones at the metaphysis and undermineralization of the shafts of bones. The term osteomalacia (“soft bones” in Greek) describes the bone shaft lesion in which hypomineralized osteoid, the organic portion of bone, is evident and leads to deformity (2,9). Other features were bowing of the legs, termed “bandy-legged” and “knock-kneed,” the typical varus and valgus deformities of the legs (Fig. 1) (10,11). Bossing of the forehead and parietal bones, protuberant and knobby wrists, and a waddling gait are characteristic (12). Children had diminished linear growth rate, muscle weakness (13), and often assumed a “tailor's position,” sitting cross-legged folded at the knees (14). Knob-like beading at the junction of the ribs and sternum was known as the “rachitic rosary.” There was a marked curvature of the arm, forearm, thigh, leg, and clavicle. Palpation of the bones caused pain. The chest often had a grooving of the lateral chest known as a Harrison or peripneumonic groove. Severe pneumonia was another feature (12,14,15).
Although primarily a disorder of infants, rickets could be found in older children during wartime (12,14,16) (Fig. 2). Although many children perished in infancy of inanition and infection, pneumonia and tuberculosis were common even in surviving children (17,18). Because of the high mortality rate, the cause of rickets was sought with vigor by pediatricians and medical investigators (8,16,19,20).
Before the discovery of vitamin D in cod liver oil, numerous theories of the cause of rickets prevailed (1,8,19). Infection, inactivity (confinement), crowded living conditions, and a consequence of tuberculosis were posited as causes (21). Koch (22) stressed his strong belief in an infectious origin. Because of the strong association between infection and rickets, as well as with active tuberculosis (21), the infectious theory was readily embraced (22,23). Findlay and Paton (24–28) and their Glasgow school theorized that the cause was confinement and crowding, prevalent in the tenements of Glasgow and Edinburgh. Rickets was generally understood to be far less common in rural-raised children (5). The children of crofters in the highlands of Scotland had rates of rickets that were much lower than urban children living in the same country (5,24–26,29,30). Other theories of the etiology of rickets included a congenital basis, a deficiency of lime salts in the diet (31), abnormalities of an organ of internal secretion, formula-feeding rather than breast-feeding, and the unhygienic conditions of the poor, all well reviewed by Zappert (32) and Findlay (25).
The nutritional hypothesis as a basis for rickets was a prevalent and persistent theory for >40 years (8,33). According to Park, a British biochemist named Francis Gowland Hopkins believed that a substance was lacking in the diet and championed the nutrition school of thought. Cod liver oil was already noted to prevent or cure rickets (8,33). First administered to children in fishing villages in Scandinavia and the Netherlands, this home therapy spread to the German, French, and English coasts. Cod liver oil was used in Manchester as early as 1766 (34) and by French and German physicians in the late 19th century. Nonetheless, skepticism persisted (35).
To appreciate the importance of an animal model of rickets in elucidating its cause, one must understand that clinical trials to prove any of the above hypotheses could not be performed, in part because controlled clinical investigations were only just being developed. Cod liver oil use as a cure was anecdotal at best, and the difference in the prevalence of rickets in urban versus rural areas was mainly an observation (5). We also now recognize that rickets had been described at the beginning of the Industrial Revolution and increased in prevalence when skies were darkened by coal smoke (3,5,36,37). With crowding increasing as people moved into cities for factory work, not only was the photocutaneous synthesis of vitamin D limited but also the dietary intake of dairy products and fish containing calcium was reduced.
A natural animal model of rickets was described, but was somewhat obscure because it was mainly alluded to in texts (25,34,38,39). The problem, put simply, was that 20 of 21 litters of lion cubs in the London Zoo perished from rickets with inanition and infection (8). In 1 case, the dam nursed for approximately 2 weeks and then experienced lactation failure. The cubs were weaned onto the then common diet of lean horsemeat and horse bones. John Bland-Sutton, a rising figure in British surgery and an active zoo surgeon, recommended a diet of goat flesh, goat bones (softer and more chewable than horse bones), and milk for the cubs and the dam. He also suggested that the cubs lick cones of cod liver oil. The cubs survived, the rickets reversed, and normal growth returned. The dam had viable litters for the remainder of her breeding career.
The second and third animal models were more logically planned. Gowland Hopkins recognized in 1910 that the guinea pig and rat did not develop rickets in short-term experiments. He knew of the oatmeal-fed puppy work of Leonard Findlay and D. Noel Paton, who reported in 1909 a cure when dogs were walked outdoors and freed from confinement (25,28,40). Hopkins encouraged his protégé, Edward Mellanby, to investigate the question using beagles fed cereal diets. This work began in 1913.
Findlay, the first chair of pediatrics at Glasgow, and Paton, a physiologist, began a series of studies feeding dogs special diets in 1911 (model 2, Table 1) in an effort to create an animal model of rickets. They preferred collies, a breed prone to rickets. They used a cereal grain base, particularly oatmeal, and the dogs were kept indoors. Findlay, however, noticed that 1 animal was “exercised outside by its prospective owner once or twice daily” and recovered from rickets despite its diet. This led to controlled trials of exercise versus confinement using larger numbers of collies, revealing that outdoor exercise compared with confinement led to the claim of a cure (24–28,41). Had they chosen to exercise the dogs indoors, the dogs would not have received curative doses of vitamin D from sunshine and their hypothesis would not have been supported.
Findlay and Paton were inspired by the remarkable crowding into tenements in Scotland's 2 largest cities, Glasgow and Edinburgh, at the height of the iron, coal, and shipbuilding era. Palm (5), a medical missionary from Edinburgh, had found that this area abounded with children with rickets. He failed to see rickets in the tropics and southern Japan, and surmised the importance of sunshine exposure (5,42).
Mellanby (43,44) is generally credited with the first animal model of rickets (model 3, Table 1). The message that Mellanby derived from the lion cub story was that their cure related to fat in the diet. From 1913 to 1921, he designed a series of experiments in beagles in which he used a high-cereal diet to produce an animal with undermineralized bones and teeth (Fig. 3) (45). The beagles were confined indoors away from the sun. Of the fats (butter, margarine, linseed oil, cod liver oil) he added to the dog diet, cod liver oil was by far the most effective in preventing or curing canine rickets (46). Ironically, dogs produce vitamin D in their skin, and dogs that groom after sunshine exposure are actually ingesting oral vitamin D supplements (47). If Mellanby's beagles had been allowed outside, he may never have discovered the nutritional component of rickets.
May Mellanby, the spouse of Edward Mellanby and a prominent dental investigator, evaluated the same dogs with regard to the effects of the grain diets on the structure of canine teeth. She was able to show the same effects on tooth enamel formation as were shown for bones by cod liver oil supplementation using the same animals (48). Tooth enamel defects were also common in infantile rickets (8,12).
When Elmer Verner McCollum left Yale after his PhD for the Wisconsin Agricultural Station on the Madison campus in 1907, he found that the subjects used there in nutrition studies were cows (49). His underlying “big hypothesis” was that a substance not ordinarily detected in the chemical analysis of animal feed at the time was deficient. Routine analysis focused on protein, carbohydrates, and lipids. Rather than feed kilograms of food to slowly growing cows and examine the viability of calves over years, he recognized the advantage of using rodents—rats or mice—whose life cycle and reproductive cycle were much shorter (49). Mice were too small, and barn rats were ferocious, so he chose the relatively mild-tempered albino rat, which he purchased from a Chicago pet store.
During his faculty stay between 1907 and 1917 at the University of Wisconsin, McCollum discovered fat-soluble vitamin A in cod liver oil, and that water-soluble vitamin B (the beri-beri factor) was necessary for the optimum growth of rats. McCollum was the first nutritionist to use the albino rat as an experimental animal (33). He also became interested in the role of various ions in the growth of rats, including sodium, potassium, calcium, and magnesium. In 1917, at the newly formed School of Hygiene and Public Health at The Johns Hopkins University, McCollum and his assistant, Nina Simmonds, formed a remarkable collaboration with John Howland, Edwards A. Park, and Paul A. Shipley and published a series of studies on experimental rickets (model 4, Table 1) (33). A crucial experiment was that aeration of cod liver oil, which destroyed all vitamin A activity, did not destroy the antirachitic factor (50). For several years, Mellanby (46) had been cautious in differentiating the antirachitic factor from vitamin A. As long as Mellanby called his deficient nutrient vitamin A or an unknown factor, the Glasgow group could claim that confinement was the key. The findings of Mellanby in beagles fed the cereal diet were reproduced in the albino rat by the McCollum team and included bone histology, growth, biochemical measurements of ions and minerals, and recognition of the importance of phosphorus in the rat diets. Many cereal diets were shown to contain phytates, which impair phosphorus absorption (8,14,51). Sherman and Pappenheimer also produced rickets in rats, a model mimicking familial hypophosphatemic rickets, which they then cured by adding inorganic phosphate to the diet.
The rats in Wisconsin were raised under tungsten lights (51). This meant that there was no skin synthesis of vitamin D, and Steenbock could irradiate rats that had never been exposed to ultraviolet B wavelengths. Recall that the beagles and collies used in experiments in London and Glasgow, respectively, were raised indoors.
Another investigator in nutrition who used animal models was Harriette Chick, who did extensive work on vitamin B1 in guinea pigs and pigeons and studied vitamin C in guinea pigs (16). Her classic studies of the prevalence of rickets were performed in children, mainly in Vienna, during a several-year period after World War I. She conducted clinical trials and established the importance of cod liver oil as a therapy for children. By this time, Park and Howland also had performed an open-label clinical trial of their own (17,18,52).
A further confusing situation arose from studies on the effect of light on rickets. Studies from Germany by Huldschinsky (53,54) showed that at the height of World War I children were cured of rickets by exposure to quartz mercury vapor lamps. These lamps permit passage of UV rays, especially wavelengths between 270 and 313 μm (UVB rays). Had he used glass, the short wavelengths would have been filtered out. Huldschinsky also showed that irradiation of 1 arm could cure rickets in the other arm. Palm (5) previously noted that at certain latitudes near the Equator rickets was less prevalent, and that natives of the region had darker skin. In terms of UV light, an instructional monograph of the Children's Bureau in 1931 went so far as to state that mothers should “begin sun baths early” and “give the baby a coat of tan” (55).
The concept that vitamin D had 2 origins, photocutaneous and dietary, was recognized by the mid-1920s (55–57). Again, a paragraph on sunlight, growth, and health in the Children's Bureau Manual stated “a child needs the sun when he is growing fastest, in babyhood and early childhood. He also needs “bottled sunshine,” or cod liver oil. If the baby does not get enough cod liver oil, he may develop rickets.” (55).
These dual themes were sometimes difficult to reconcile. Dietary intervention with fat, preferably cod liver oil, was clearly curative. Moreover, it was hard to understand the importance of sunlight as a cure and a prophylactic strategy in children, but not in animals. Ultimately, it became clear that the relatively hairless and amelanotic white rats could derive vitamin D from either a dietary or photocutaneous source (38). Rats and dogs could derive some vitamin D from their skin, but many carnivores could not (47). In most experiments, rats or dogs were kept in dimly lit rooms with glass windows, which would have filtered the short wavelengths needed for photocutaneous synthesis of vitamin D (58).
Reaction to the studies of Mellanby and McCollum's group had come initially from Findlay and Paton and the Glasgow school (24,27,59). They continued to view rickets as the result of a lack of exercise and fresh air and advocated massage. Although these views were held in the early 1920s, the importance of nutrition and a fat-soluble vitamin was dictum by 1927 and 1928 (16,46,50). Findlay finally conceded that the oatmeal diet was rachitogenic (39).
In 1927, synthesis of an antirachitic factor by UV irradiation of ergosterol was stimulated by the observations of Huldschinsky (53,54), and investigators showed that irradiation of food and/or skin produced a factor that McCollum had termed vitamin D (8,56,57). The work of Hess (56,60) in the photobiology of vitamin D was a crucial leap forward to fully conceptualize rickets. Simultaneously, Steenbock (51) at Wisconsin found that UV irradiation of the food-fed rats was curative. This body of work led to 2 further animal models.
An animal model of rickets (model 5, Table 1) was studied by New York pediatrician Alfred Fabian Hess (1875–1933). Hess was interested in nutritional deficiencies, including scurvy and rickets, and ran a laboratory from 1917 to the end of his life in 1933. He enlisted the help of Windaus (56), a German chemist who was an expert on the structure of cholesterol and steroid compounds. By 1927, they had found that vitamin D was not cholesterol, and that the steroid ergosterol, when irradiated by UV light, formed ergocalciferol (vitamin D2), which could cure rickets in rats with as little as 0.003 mg/day per rat. Independently, Harry Steenbock at the University of Wisconsin-Madison irradiated first the food and then the skin of rats, and suggested that UV irradiation could cure or prevent rickets (model 6, Table 1). He ultimately suggested adding ergocalciferol to milk, which was the key method of preventing rickets in children (51). In 1929, Windaus (61) won the Nobel Prize for his studies of cholesterol and other sterols, culminating with a description of the structure of vitamin D.
The “study” of lion cubs in the London Zoological Gardens was not generally recognized as an animal model of disease. In reality, John Bland-Sutton was fortunate that his diet worked to cure rickets. The attempt to reverse rickets in lion cubs was an open-label, uncontrolled interventional experiment. Its essential value was encouraging other investigators to design studies that explored the role of nutrients in the pathogenesis and treatment of rickets and osteomalacia (1,8). Park (8), of the Baltimore team, felt that the true worth of Bland-Sutton's work was somewhat overblown. He stated, “The so-called experiments of Bland-Sutton have had an influence which apparently they have not merited.” In addition, Park pointed out that sometimes lions upon maturation “presented remarkable rickety changes in their skulls.” Despite Park's reservations, numerous investigators of vitamin D deficiency in addition to Mellanby (2,8,25,62) recognized that the lion cubs in the London Zoo represented the initial animal experimental model of rickets.
Other factors are critical to the diet of big cats such as lions, tigers, and leopards (63). Cats fail to synthesize vitamin D3 adequately in the skin and, hence, require a dietary source (63–67). Felines also lack the ability to convert provitamin carotenoids, including β-carotene, into active vitamin A (68). Vitamin A is important to the integrity of the epithelium of the respiratory and digestive tracts. Vitamin A deficiency in large cats can lead to sinusitis, diarrhea, blindness, conjunctivitis, and neurologic signs (63).
Big cats eat whole animals or are given bones. They ingest calcium and phosphorus in a ratio of 2 parts calcium to 1 part phosphorus. Lean meat has a calcium:phosphorus ratio of 1:15 to 1:30. Large cats with low calcium intake can develop osteomalacia, and their diets should be fortified with calcium (63). Cubs are able to chew softer bones, such as those of goats, rather than the hard bones of horses (8). The great cats are obligate carnivores, as are their domestic short-haired cousins. Felines have limited amounts of cysteine sulfinic acid decarboxylase, a rate-limiting synthetic step in the synthesis of taurine from methionine and cysteine (69). Hence, taurine is an essential amino acid in all of the cats. Cats fed a vegetable protein diet require taurine to prevent retinal degeneration and blindness (69,70). Also, the chunk horsemeat diet of exotic felines contains low taurine concentrations (71). Goat meat has higher taurine levels.
Cod liver oil is replete with vitamin A and D, with a conventional value of 4000 to 5000 IU of A and 400 to 500 IU of D per teaspoonful (5 mL) (72). To be used, however, these fat-soluble vitamins require intestinal absorption. Bile salts are essential to this biologic phenomenon and are contained in cod liver oil. The conjugation of bile acids, especially those in herring (73) and cod (74), and in the great cats, is dependent on the availability of taurine (72,73). When cod liver oil was processed in 1889 by extraction from fish liver at 82°F or under steam, both taurine and bile acids were available (75). This supplement contained not only the vitamins but also the bile acids that break down lipid micelles and permit intestinal fat absorption (20,75). Moreover, cod, typical of marine fish, have high taurine content and use it as an osmolyte, which is essential for cell volume regulation (20,76,77).
Cholic acid is by far the dominant bile acid of lions (78). Taurine conjugation of bile acids is mandatory because glycine conjugation does not occur as it does in rats or dogs (20,69,78,79). Therefore, by providing cod liver oil to the lion cubs, Bland-Sutton also increased their dietary intake of bile acids and taurine. This promoted absorption of fat-soluble vitamins (2,62).
The photocutaneous synthesis of vitamin D is irrelevant in the lion, which is dependent upon dietary sources of vitamin D (47). Because reversal of rickets came following the addition of fat to the lion cubs’ diets, some interpreted the Bland-Sutton experiments as demonstrating the value of adding fat to a protein or milk diet in children (8,62).
Mellanby wisely chose puppies, and McCollum, another farm boy, chose rats, which were far easier to study. Hess and Steenbock also used rats. In trying to save rachitic lion cubs, Bland-Sutton had run into a species that needed calcium and phosphorus from bones, and for whom taurine is an essential amino acid. Cod liver oil provided both the necessary vitamins and the taurine required for conjugating bile acids for intestinal fat-soluble vitamin absorption. Bland-Sutton was indeed fortunate in his choice of dietary supplements.
In conclusion, the animal model of John Bland-Sutton can be claimed as the initial animal model of rickets. The model was recognized by Paton and Watson and inspired Edward Mellanby. The Mellanby, McCollum, Park, Shipley, Hess and Steenbock studies were well controlled and precisely conducted. Along with the irradiation studies of Hess and Steenbock, which showed that UV rays could add vitamin D activity to foods and skin, these studies led to the basic observations concerning either dietary or photocutaneous synthesis of vitamin D. Although the model of Bland-Sutton's lion cubs could be dismissed as incomplete, and the rival theories of Findlay and Mellanby lacked definitive answers, the McCollum, Park, and Shipley group clearly showed that a missing nutrient, vitamin D, could reverse and prevent rickets. Each model was important.
The biochemistry and molecular and cellular biology of vitamin D has been a major biological and biomedical theme since 1965 (2,62,80). Today, scientists use transgenic, knock-out, and knock-down technology to define the myriad effects of vitamin D in health and disease (81–85). In the background are the tales, broadcast online and in brochures, concerning lions in private zoos in 2005 who developed rickets and vitamin D deficiency when fed improper diets. The observations of John Bland-Sutton are as important today as they were in 1889.
I am grateful to Andrea Patters for assistance with the manuscript.
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