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 metabo- lite 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 ani- mals’ 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.