Unraveling the Enigma of Vitamin D, October 2000

This article was published in 2000 and has not been updated or revised. BEYONDBEYOND DISCOVERYDISCOVERYTM

THE PATH FROM RESEARCH TO HUMAN BENEFIT UNRAVELING THE ENIGMA OF VITAMIN D

ost of us know that to maintain good health Boomers celebrate their fiftieth-plus birthdays, concerns we need to eat a balanced diet that includes about the brittle bones and fractures associated with M fruits, vegetables, grains, protein, and some advanced age are focusing renewed attention on vitamin fat. In this age of fast food and missed meals, however, D. Increasingly, researchers are learning that vitamin many of us also take supplements to ensure that we’re D is essential in maintaining health and preventing dis- getting the minimum daily requirement of essential vit- ease not just during the crucial growing years of child- amins and minerals—nutrients necessary only in very hood but throughout life. Recent studies show that vita- small quantities to prevent disease and to keep us opti- min D insufficiency may even be, in one researcher’s mally healthy. words, “an unrecognized epidemic” among both women The first of these so-called micronutrients was discov- and men, who are middle aged and older. In addition ered a little over a century ago, with investigations into to affecting bone growth, scientists are finding that vita- the causes of such diseases as scurvy, beriberi, and rickets. min D and calcium may affect diseases and disorders as The following article focuses on the twists and turns disparate as colon cancer, multiple sclerosis, premenstrual leading to the discovery and understanding of one such syndrome, psoriasis, high blood pressure, and depression. nutrient: vitamin D, a substance that occurs naturally in only a few foods and that is also manufactured in the skin when a precursor interacts with the short ultraviolet rays of the sun. A Case of Mistaken Without adequate levels of 1,25-dihy- Identity droxyvitamin D3—the active metabolite of vitamin D—in the blood, the One of the reasons vitamin D was body cannot absorb and use the dietary a puzzle to scientists for so many years calcium essential for such vital func- was that it was initially misidentified as tions as the electrochemical signaling a true vitamin, that is an essential sub- between brain cells. When dietary cal- stance that our bodies cannot manu- cium and the mineral phosphorus are facture and which, therefore, can only not properly absorbed through the intes- be obtained from our food. But tine, the body also cannot build strong unlike essential dietary trace elements, bones. In children, vitamin D deficien- As seen in this X-ray image, the such as vitamins A, B, and C, which cy results in the once common disease bones of a child with rickets, which humans must get directly from food, known as rickets, which leaves its life- prevents the conversion of soft vitamin D can be produced in the long mark of bowed legs and deformed cartilage to healthy bone, bow body through a photosynthetic reac- under the child’s increasing ribs. In adults, the result is the bone weight. (Michael R. Richardson, tion when the skin is exposed to sun- disease osteoporosis. University of Washington light. The resulting substance is only Today, as growing numbers of Baby Department of Radiology) a precursor, however, which must

NATIONAL ACADEMY OF SCIENCES then undergo two transformations—first in the liver outdoor life of the farm for factory work in the and then in the kidney—to become the biologically smoggy air of industrial cities, rickets had become a active substance the body uses. This active form of plague all over Europe. Symptoms of the disease vitamin D is a hormone, chemically akin to familiar were unmistakable. The bones of afflicted infants steroid hormones, such as the sex regulators testos- remained soft, like cartilage, and the babies were terone and estrogen and the stress regulator cortisol. slow to sit, crawl, and walk. As the children grew, Arriving at a clear understanding of the multifac- their soft bones bent under the additional weight, eted nature of vitamin D and its role in the body— leaving the children with rickets’ telltale pigeon especially its relationship to calcium—was the culmi- breast, bowed legs, or knock-knees. Rachitic chil- nation of three different avenues of research. The ear- dren (that is, children with rickets) also suffered from liest investigators were interested in the causes and tetany: painful spasms of the hands, feet, and larynx, prevention of particular diseases, such as scurvy, along with difficulty in breathing, nausea, and con- beriberi, and rickets. On a separate track, scientists vulsions. This condition, later found to be sympto- were examining how the known primary constituents matic of insufficient calcium, was often so severe that of food (proteins, fats, carbohydrates, salts, and water) children died. affected health and growth. Work along these two Throughout the nineteenth century, sporadic fronts dovetailed to yield the concept of vitamins—an reports of cures for rickets surfaced, but with little essential micronutrient in food—and to establish that effect. In 1822, for example, a Polish physician vitamin deficiencies can lead to disease. This allowed observed that children in Warsaw suffered severely a lack of vitamin D to be identified as the cause of from rickets, whereas the disease was virtually rickets. But many aspects of this “vitamin” remained unknown in the city’s rural outskirts. After experi- baffling, since it was actually a hormone whose active menting with the two groups, he concluded that sun- form is produced in our bodies in response to regula- bathing cured rickets. Five years later, a French tory signals. An understanding of the vitamin D hor- researcher reported cures among those given the mone and its roles in human physiology would home remedy cod-liver oil. Neither treatment gained require the knowledge and tools of a third line of widespread attention, in part because the prevailing research that had been developed by organic chemists medical wisdom was that people needed only to get studying sterols—the steroid alcohols (such as choles- adequate amounts of the so-called macronutrients— terol) that occur in both animal and plant fats. Just as proteins, fats, and carbohydrates—in order to maintain a tapestry image emerges from the weaving of many health. However, researchers looking into the causes threads, clues from each line of inquiry eventually of such diseases as pellagra and beriberi began to sus- formed a pattern that solved the enigma of vitamin D. pect that the macronutrients might not be the whole story—that, in fact, there was more to ordinary food than met the eye.

Tracing the Cause of Disease The first solid hint that a specific dietary deficiency “. . . a substance different could lead to disease came in 1754. In that year the from protein and salts . . .” Scottish naval surgeon James Lind showed that scurvy—the painful and sometimes fatal bane of In the late 1880s Dutch physician Christiaan mariners on long ocean voyages—could not only be Eijkman was sent to the East Indies (now Indonesia) cured but also prevented with the juice of oranges, to investigate why beriberi was so widespread in the lemons, and limes. By the late eighteenth century, region. Eijkman observed that hens in his Jakarta lab- British sailors (soon nicknamed “Limeys”) were reap- oratory suffered symptoms of nerve disease (polyneu- ing the benefit of Lind’s discovery. ritis) that were strikingly similar to those for beriberi— Meanwhile, the advent of the Industrial including muscle weakness, nerve degeneration, and Revolution in Britain in the late 1700s brought with paralysis. He then began a series of experiments to try it a different scourge: rickets. The disease itself had to find a culprit organism, which he assumed was the first been described by physicians in the mid 1600s, cause. (Like most of his contemporaries, Eijkman was but it was then relatively rare. By the nineteenth influenced by the work of Louis Pasteur and believed century, however, as more and more families left the that a bacterium caused beriberi.)

2 BEYOND DISCOVERY This article was published in 2000 and has not been updated or revised. Eijkman failed in this effort, but in 1897 he did Hopkins and Christiaan Eijkman—in belated recogni- succeed in establishing something more significant. tion of his seminal work with beriberi—would later He showed that the hens contracted the beriberilike share the 1929 Nobel Prize for Physiology or polyneuritis soon after their feed was changed to pol- Medicine for the discovery of essential nutrient factors. ished rice—that is, rice whose outer husk had been At about the same time that Hopkins was demon- removed. He also proved that by adding rice bran strating the existence of vitamins, other researchers (the parts removed in polishing) to the hens’ food, were investigating the effects of different diets on the the disease could be cured. health of experimental animals. Over the next two Eijkman and his successor, Gerrit Grijns, later used decades, they would identify a number of vitamins, water or ethanol to extract the mysterious antineuritic demonstrating again and again that these essential nu- factor from rice hulls. “There is present in rice pol- trients are not equally distributed in the foods we eat. ishings a substance different from protein and salts,” In 1913, for example, Wisconsin researchers Elmer the two researchers wrote in 1906, “which is indis- McCollum and Marguerite Davis discovered a fat- pensable to health and the lack of which causes nutri- soluble accessory substance. By feeding rats diets of tional polyneuritis.” different foods and observing the effects on the animals’ growth and health, McCollum and Davis found Dutch physician Christiaan Eijkman that the new substance is present in egg yolk and but- demonstrated the rela- ter fat but absent from lard and other fats. They called tionship between the nutrient “fat-soluble vitamin A.” These scientists nutritional deficiency were further able to show that vitamin A in the diet and disease through prevents night blindness and the eye disease xeroph- his studies of beriberi in Indonesia during thalmia. The team of L. B. Mendel and T. B. Osborne the late nineteenth independently published similar results within weeks. century—work that earned him the 1929 Nobel Prize for Physiology or Medicine. (The Nobel Closing in on Rickets Foundation) By this time, a number of studies had focused attention again on rickets, which was still a severe In 1926 B. C. P. Jansen and W. Donath, two Dutch problem in Scotland and in parts of northern Europe. chemists working in Eijkman’s old laboratory in Jakarta, A few investigators approaching the question from crystallized the water-soluble antineuritic factor—now another direction had picked up the nearly forgotten called vitamin B 1, or thiamin—from rice bran. clue about the effectiveness of sunlight. In 1892, Another researcher soon after the turn of the cen- British scientist T. A. Palm found a relationship tury also came to believe in the existence of certain between the geographic distribution of rickets and “accessory food factors.” English biologist Sir the amount of sunlight in the region. In 1913, Frederick Gowland Hopkins developed this concept in University of Wisconsin’s H. Steenbock and E. B. the course of work that began with his discovery in Hart made a more direct link, showing that lactating 1901 of the amino acid tryptophan. Building on tech- goats kept indoors lose a great deal of their skeletal niques developed in this research, Hopkins went on to calcium, whereas those kept outdoors do not. Six perform a series of now classic experiments demon- years later, in 1919, the German researcher K. strating that whole foods (as opposed to purified forms Huldschinsky carried out a remarkably innovative of proteins, fats, and carbohydrates) contain certain experiment and cured children of rickets using artifi- unknown constituents essential to health and growth. cially-produced ultraviolet light. Two years after that, Biochemist Casimir Funk, whose own work led researchers Alfred F. Hess and L. F. Unger of him to believe these factors were amines (compounds Columbia University showed that by simply exposing derived from ammonia), suggested they be called rachitic children to sunlight, they were able to cure “vital amines” or “vitamines” for short. The “e” was them of the disease. later dropped when scientists realized that these vari- On the nutritional front, in the meantime, British ous nutrients have different chemical properties and physician Sir Edward Mellanby, still searching for a functions and that many contain no amines at all. dietary deficiency as the cause of rickets, decided in

NATIONAL ACADEMY OF SCIENCES 3 This article was published in 2000 and has not been updated or revised. 1918 to test porridge, the staple food of Scotland, by First at the University feeding dogs exclusively on oats. Inadvertently, he of Wisconsin, and also kept the animals indoors throughout the experi- later at Johns Hopkins ment, thereby inducing rickets. When he cured the University, Elmer V. McCollum carried out dogs of the disease by feeding them cod-liver oil, seminal research estab- Mellanby naturally credited the oil’s recently identi- lishing the existence of fied vitamin A with the cure. the vitamin B com- On learning of Mellanby’s experiments, plex, vitamin A, and McCollum, who had since moved from Wisconsin to vitamin D. (The Johns Hopkins University in Baltimore, decided to National Academy of Sciences) pursue them further. From his own work on isolating vitamin A, McCollum had found that certain foods may contain more than one accessory food substance. He thus designed a series of ingenious experiments to follow up on Mellanby’s findings and discover what else, if anything, cod-liver oil might have to offer. He intractable. Although physicians knew that sunlight began by heating and aerating the oil to destroy its was essential for young bones, the streets of industrial vitamin A. As expected, the treated oil no longer cities were as smoky and sunless as ever. And chang- cured night blindness. But, to everyone’s surprise, it ing people’s dietary habits to include prescriptive did remain effective against rickets. Clearly, an doses of cod-liver oil was no easy matter. unknown essential nutrient was responsible. In his Then came a series of experiments that tied 1922 publication of these experiments, McCollum fol- together the nutritional research and the findings lowed the designations of vitamins in alphabetic order; concerning irradiation, offering a solution to this crit- since vitamins B and C had recently been named, he ical piece of the vitamin D puzzle and paving the way dubbed the new miracle worker “vitamin D.” for a widely available cure for rickets. During the By the early 1920s, then, it appeared that the course of extensive nutritional research, Harry world had two cures for rickets: cod-liver oil and irra- Goldblatt and Katherine Soames, working in London, dation—that is, exposure to sunlight or ultraviolet discovered that the livers from irradiated rats, when light. Despite this promise, the disease remained fed to other rats were growth promoting, whereas the

Timeline This timeline shows the chain of research and events that led to an understanding of vitamin D in biological systems and to the development of some of its medical uses.

Early 1900s Early 1920s 1927 Sir Frederick Gowland Hopkins 1918 Harry Goldblatt and Katherine Soames, Adolf Windaus, O. demonstrates that whole foods Sir Edward Mellanby H. Steenbock and A. Black, and Alfred Rosenheim, and T. A. (as opposed to purified pro- induces rickets in dogs Hess and Mildred Weinstock indepen- Webster deduce that teins, fats, and carbohydrates) and then cures the dis- dently discover that irradiating certain ergosterol is the likely contain certain unknown con- ease by feeding the foodstuffs with ultraviolet light renders parent substance of stituents essential to health animals cod-liver oil. those foods antirachitic. vitamin D in food. and growth.

1919 1922 Mid 1600s 1906 K. Huldschinsky cures Elmer V. McCollum 1931 Rickets is first Christiaan Eijkman and Gerrit children of rickets using destroys vitamin A in cod- F. A. Askew defines the described. Grijns extract the antineuritic artificially produced liver oil and shows that chemical makeup of the factor from rice hulls, later ultraviolet light. the separate antirachitic form of vitamin D found in shown to be vitamin B1. substance remains. He irradiated foods (now calls the newly identified called ergocalciferol), substance “vitamin D.” derived from the precursor molecule ergosterol.

This article was published in 2000 and has not been updated or revised. livers from unirradiated rats were not. In the early dren began consuming irradiated milk and bread and, 1920s, two teams of researchers—H. Steenbock and seemingly overnight, the imminent threat of epidemic A. Black, and Alfred Hess and Mildred Weinstock— disease dwindled to a half-forgotten historical event. followed up on this strand of research, as well as But the quest to understand vitamin D was only just Huldschinsky’s lead, by further experimenting with beginning, for scientists still knew almost nothing of the effect of ultraviolet light on foods fed to rats. what it was or how it worked. Independently, the two teams of researchers irradi- The search continued for the exact substance in ated excised skin as well as such food substances as food and skin that was activated by ultraviolet irradia- vegetable oils, egg yolk, milk, lettuce, or rat chow and tion. Several teams of researchers—Wisconsin’s found that irradiation produced a substance that Steenbock and Black; Columbia University’s Hess, seemed to work on rickets much as the vitamin D in Weinstock, and F. Dorothy Helman; and O. cod-liver oil did. Rats that were fed irradiated foods or Rosenheim and T. A. Webster of the National Institute irradiated skin were protected against rickets, whereas for Medical Research in London—confirmed that the those fed unirradiated foods or skin were not. Recog- substance is present in animal and vegetable fats. nizing that simply irradiating certain foods that were Moreover, they proved that it is localized in the frac- common in most people’s diets could spare large num- tion of fats known to contain sterol molecules. The bers of children from the bone disease, Steenbock researchers found that purified cholesterol (a major patented the food irradiation process using ultraviolet animal sterol) and phytosterols (vegetable sterols), light in 1924, donating all future proceeds to support both of which otherwise have no antirachitic proper- research at the University of Wisconsin. ties, are rendered antirachitic by ultraviolet irradiation. Up to this point, researchers investigating vitamin D had to be content with characterizing the elusive substance on the basis of its physiological effects. As it happened, however, the work of organic chemist Animal, Vegetable, or Adolf Windaus, in Göttingen, Germany, would pro- Mineral? duce chemical tools that would finally help pinpoint the molecular identity of vitamin D. Early in the cen- By 1924, the practical side of the battle against tury, Windaus had embarked on his study of choles- rickets had been won. Across the United States, chil- terol and related sterols, about which virtually noth-

1980s 1968–1970 A Japanese research team The existence of a second 1975 and, independently, Michael 1994 active metabolite produced F. Holick and coworkers 1936 Haussler confirms The U.S. Food and from 25-hydroxyvitamin D show that vitamin D hor- Windaus deduces the 3 the discovery of a Drug Administration is reported by Anthony W. mone inhibits skin cell chemical structure of vit- protein receptor that approves a vitamin Norman, Mark R. Haussler, growth. Holick and col- amin D3 produced in the binds the active vita- D–based topical treat- and J. F. Myrtle; by E. leagues demonstrate that skin (now known as min D metabolite to ment for psoriasis, Kodicek, D. E. M. Lawson, topical applications of the cholecalciferol) and iden- the nucleus of cells called calcipotriol. tifies the structure of its and P. W. Wilson; and by in the intestine. vitamin D hormone are a parent molecule, 7-dehy- DeLuca and coworkers. remarkably effective treat- drocholesterol. ment of psoriasis.

1971 Mid 1980s 1970s 1968 Three research groups identify Researchers find that the chemical/molecular struc- Researchers discover the Hector F. DeLuca and colleagues iso- vitamin D hormone ture of the final active form of relationship of vitamin D to late an active vitamin D metabolite seems to play a part vitamin D as 1,25-dihydroxyvit- the body’s endocrine system and identify it as 25-hydroxyvitamin in modulating the amin D , which is soon reclas- and calcium regulation. D . They later prove that the sub- 3 immune system. 3 sified as a hormone controlling stance is produced in the liver. calcium metabolism.

This article was published in 2000 and has not been updated or revised. ing was known at the time. From the very start, he worked. Over the next forty years, a number of believed that sterols, which occur in every cell, must research teams teased out vitamin D’s metabolic path- be considered as the parent substance of other groups way in the body. One of the confusing initial findings of natural substances, and he was convinced that was that the metabolic by-products of vitamin D all investigations into the structure of these molecules seemed to be biologically inactive. How, then, did would yield unexpected results. vitamin D build bone and cure rickets? By 1925, Windaus was recognized as the leading Scientists did not have the tools to follow this expert on sterols, and Hess invited him to come to complicated process in living subjects until the advent, New York to work on antirachitic vitamins. Windaus in the mid 1960s, of new techniques using radioac- also was collaborating with Rosenheim and Webster in tively labeled substances. Between 1968 and 1971, London at the time, and in 1927 both teams, using a researchers made great progress in understanding the series of clever chemical transformations and compar- metabolic processing of vitamin D and its physiologi- isons with known compounds, deduced that ergosterol cal activity. In 1968, a team headed by Hector F. was the likely parent substance of vitamin D in food. DeLuca at the University of Wisconsin isolated an Back in his own laboratory in Göttingen the following active substance identified as 25-hydroxyvitamin D3, year, Windaus isolated three forms of the vitamin: two which the team later proved to be produced in the derived from irradiated plant sterols, which he called liver. During the next two years, the Wisconsin team, D1 and D2, and one derived from irradiated skin, Anthony W. Norman and colleagues at the University which he called D3. F. A. Askew’s British team fol- of California-Riverside, and E. Kodicek and coworkers lowed up in 1931, successfully defining the chemical at Cambridge University in England independently makeup of D2—the form of vitamin D found in irradi- reported the existence of a second active metabolite. ated foods (now called ergocalciferol)—which was Kodicek and David R. Fraser showed that this second derived from the precursor molecule ergosterol. Five metabolite is produced in the kidney. Finally, in 1971 years later, in 1936, Windaus synthesized the molecule all three research groups published papers in which 7-dehydrocholesterol and then converted it by irradia- they reported the chemical/molecular structure of tion to vitamin D3, now known as cholecalciferol. this metabolite, which was identified as 1,25-dihy- Although it was assumed that vitamin D was photo- droxyvitamin D3. It was now clear that the liver synthesized in the skin from 7-dehydrocholesterol, the changes vitamin D3 to 25-hydroxyvitamin D3, the final proof did not emerge until more than three major circulating form of the vitamin. The kidneys decades later. A Wisconsin team led by R. P. Esvelt then convert 25-hydroxyvitamin D3 to 1,25-dihy- and one led by Michael F. Holick at the Endocrine droxyvitamin D3, the active form of the vitamin. Unit of Massachusetts General Hospital then indepen- But how does all of this affect calcium deposition dently demonstrated that vitamin D3 is, in fact, what to build strong bones? Since the 1950s, scientists had is produced in the skin through irradiation. been puzzling over the implications of two findings Because of these discoveries, it became possible related to this question. In the early part of that to synthesize the vitamin in large quantities. Syn- decade, the Swedish researcher Arvid Carlsson made thesizing the vitamin costs a fraction of what it costs the startling discovery that vitamin D can actually to irradiate foods and does not destroy or change remove calcium from bones when it is needed by the food flavors, as irradiation sometimes does. Synthe- body. At about the same time, the Norwegian bio- sized vitamin D provided the capstone of the public chemist R. Nicolaysen, who had been testing different health campaign to eradicate rickets. For his diets on animals for years, concluded that the uptake “research into the constitution of the sterols and of calcium from food is guided by some unknown their connection with the vitamins,” Windaus was “endogenous factor” that alerts the intestines to the awarded the Nobel Prize for Chemistry in 1928. body’s calcium needs. Answers began to emerge with the experiments tracing the activation of vitamin D. An important result of those experiments was that 1,25-dihydroxyvitamin D3, the active form of vitamin D, was reclassified as a hormone that controlled calci- Vitamin D’s Connection to um metabolism. A hormone is a chemical substance Calcium Control produced by one organ and then transported in the bloodstream to a target organ, where it causes a spe- With rickets under control, scientists now concen- cific biological action. Evidence for reclassifying the trated on finding out how the miracle bone builder

6 BEYOND DISCOVERY This article was published in 2000 and has not been updated or revised. active form of vitamin D came with the realization that 1,25-dihydroxyvitamin D3 is produced by the kidneys and that its secretion by the kidneys is followed by its build up in cell nuclei of the intestine, where it regulates calcium metabolism. By 1975, Mark R. Haussler at the University of Arizona Foods confirmed the discovery of a protein receptor that binds the active vitamin D Previtamin D3 ultraviolet light metabolite to the nucleus of cells in the + intestine. Vitamin D3 7-dehydrocholesterol With vitamin D now linked to the (an inactive form) (a cholesterol precursor) intestine, scientists were zeroing in on the mechanism of calcium control. 1, 25-dihydroxyvitamin D 25-hydroxyvitamin D 3 Researchers noted that as the level of 3 (active form) (circulating form) calcium in the diet rises, the amount of active vitamin D hormone in the body falls, and vice versa—a feedback-loop pattern that clearly pointed to the vitamin D hormone as Nicolaysen’s calcium-regulating “endogenous factor.” Many research teams, including those at the University of Wisconsin and Cambridge University, now focused on The Vitamin D cycle. As illustrated here, humans can get a precursor (inac- tracing the relationship of vitamin D tive) form of vitamin D from food and also from the photosynthetic reaction that occurs when 7-dehydrocholesterol in skin cells is exposed to ultraviolet light. hormone to the rest of the body’s This inactive precursor travels to the liver, where it is changed to 25-hydroxyvit- endocrine system. They found that a amin D3, the major circulating form of vitamin D3. The kidneys, in turn, hormone produced by the parathyroid convert this intermediate form of the vitamin to 1,25-dihydroxyvitamin D3— gland is critical to maintaining adequate a hormone that not only controls calcium metabolism by increasing intestinal levels of vitamin D hormone in the calcium absorption and bone calcium mobilization, but also has many other effects throughout the body. blood. When calcium is needed, the parathyroid gland sends the parathyroid hormone to the kidneys to trigger production of vitamin D hormone. That hormone, in turn, prompts the intestines to transfer calcium from food to the More Than Just a Way to blood. When calcium intake is too small to support Regulate Calcium normal functions, both vitamin D and the parathyroid hormone trigger a process in which stored calcium is Now that its role in calcium uptake had been mobilized from the bones (confirming the Swedish sketched out, researchers in the 1970s began investi- finding nearly twenty years earlier). gating vitamin D in greater detail—and with surpris- Regulating blood calcium levels is important. ing results. Several groups managed to find the vita- When there is too little calcium in the blood, soft-tis- min D hormone in the nucleus of cells that were not sue cells—especially nerves and muscle—shut down, part of the classical calcium maintenance system sending the body into convulsions; when there is too including the brain, lymphocytes (infection fighting much calcium in the blood, organs calcify and eventu- white blood cells), skin, and malignant tissues. What ally cease to work. For human patients who had lost business would vitamin D have in these places? their parathyroid glands or their kidneys and could no In the early 1980s, Japanese researcher Tatsuo longer regulate the level of calcium in their blood, the Suda made the exciting discovery that adding the newly synthesized vitamin D hormone, when given hormone to immature malignant leukemia cells with plenty of calcium, had a dramatic effect, curing caused the cells to differentiate, mature, and stop them of convulsions and chronic bone disease. growing. The amount of vitamin D hormone needed

NATIONAL ACADEMY OF SCIENCES 7

This article was published in 2000 and has not been updated or revised. to stop the runaway growth of tumors and cancers inhibition further and reasoned that it could be used has so far proved too toxic for human use, but Suda’s for the treatment of psoriasis. discovery suggested that this fascinating hormone had Initial experiments by Holick and coworkers with roles beyond the part it played in maintaining the vitamin D hormone have shown that topical applica- body’s calcium levels. This finding spurred on a new tions of the hormone are remarkably effective. After era in vitamin D research. two months, the lesions of 96.5 percent of the In the mid 1980s, a group of researchers led by S. patients treated with a topical calcitriol (vitamin D C. Manolagas found that vitamin D hormone also hormone) preparation had improved with no notice- seemed to play a part in modulating the immune sys- able side effects, as compared with 15.5 percent of tem. In 1993, S. Yang and other researchers in the controls treated with petroleum alone. In 1994, DeLuca’s laboratory found that rats given a large the U.S. Food and Drug Administration approved a dose of vitamin D hormone were protected from the vitamin D–based topical treatment for psoriasis, called inflammation normally associated with wounds and calcipotriol. chemical irritants. This unexpected immunosuppres- As we enter the twenty-first century, we recognize sant function for vitamin D hormone suggested a that the basic scientific research done in the previous whole new range of possibilities—including its use in two centuries has not only untangled the workings of the control of autoimmune diseases. the elusive vitamin D hormone, but has also given us More developed is vitamin D hormone’s effect on ways to protect the health of both adults and chil- psoriasis, a disfiguring skin disorder that affects some dren. Researchers are pursuing many new applica- 50 million people worldwide. For reasons unknown, tions for vitamin D, but its role in building and main- psoriasis causes skin cells to multiply uncontrollably. taining bone continues to be an important health Failing to differentiate and develop normally, the skin issue, especially among middle-aged and older adults. cells clump in unsightly rashes, scales, and scars. In the 1980s, a Japanese research team demonstrated that 1,25-dihydroxyvitamin D3 can inhibit skin cell growth. This article, which was published in 2000 and has not A team of scientists at Boston University School of been updated or revised, was written by science writers Medicine, led by Michael F. Holick, investigated this Roberta Conlan and Elizabeth Sherman, with the assistance of Drs. David R. Fraser, Mark R. Haussler, Michael F. Holick, Robert Neer, Anthony W. Norman, and Munro Peacock for Beyond DiscoveryTM: The Path from Research to Human Benefit, a project of the National Academy of Sciences. The Academy, located in Washington, D.C., is a soci- ety of distinguished scholars engaged in scientific and engineering research, dedicated to the use of science and technology for the public welfare. For more than a century it has provided independent, objective scientific advice to the nation.

Funding for this article was provided by the Camille and Henry Dreyfus Foundation and the National Academy of Sciences.

The discovery that Vitamin D is present in the nuclei of cells in many different tissues of the body has led scientists to begin exploring a variety of new applications, further revealing the potential benefits of this once enigmatic hormone. © 2000 by the National Academy of Sciences October 2000

8 BEYOND DISCOVERY This article was published in 2000 and has not been updated or revised.