Albert Lasker
Clinical Medical Research Award

Presentation of Clinical Award

Humans lack the genes necessary to synthesize 14 molecules that are required for normal function of the body. These 14 essential molecules are known as vitamins—vitamin A, vitamin B12, vitamin E, folic acid, etc. All 14 vitamins must be obtained from our diet or else severe symptoms of disease will occur.

Deficiency of vitamin A is one of the world's oldest known medical conditions. It produces a spectrum of eye abnormalities that starts with night blindness and progresses to dryness and inflammation of the conjunctiva, ulceration of the cornea, and eventually to permanent blindness. 3500 years ago, the ancient Egyptians described night blindness in infants and recognized that it could be successfully treated with liver extracts, including cod liver oil. In the late 18th century, European physicians recognized that night blindness was often associated with conjunctival and corneal lesions, and like the Egyptians they, too, recognized the curative effects of cod liver oil. We now know that the active principle in cod liver oil is vitamin A and that cod liver oil is one of the richest sources of vitamin A in nature.

Our 1997 Lasker Clinical Research Award recipient is a 20th century ophthalmologist who has shed new light on an old disease. Today, we honor Alfred Sommer for his pioneering epidemiological studies of vitamin A deficiency that have saved not only the eyesight but the very lives of millions of children in the third world. As you'll hear in a moment, Dr. Sommer's studies have also revealed a new function for vitamin A in the immune defense against infectious diseases.

But first, what is vitamin A and how was it discovered? The story begins in 1907 when Elmer McCollum, a young Ph.D. chemist from Yale, was hired by the Agricultural College of the University of Wisconsin to solve the problem of malnutrition in cows. When cows were fed a diet lacking all fat, they developed night blindness and corneal ulceration. McCollum's job was to figure out how these eye abnormalities were produced by a fat-free diet. In 1907, no one had ever done a scientific study on nutrition. McCollum conceived the plan of putting animals on a chemically defined diet and then supplementing it with pure chemicals one at a time until the symptoms disappeared. He realized that the cow was not the perfect animal model for nutritional studies where hundreds of variables needed to be tested. A smaller animal was needed, and McCollum decided to use rats, which had never before been used for biomedical research. The professor in charge was astonished by the idea, telling McCollum that rats were pests and it would not be proper to spend state and federal money to cure dietary deficiencies in rats. Fortunately, the dean at Wisconsin overruled the professor. McCollum then ordered 12 albino rats, which was the beginning of the world's first rat colony for biomedical research.

Like cows, rats developed night blindness and corneal ulcers when fed a fat-free diet. These abnormalities disappeared when the fat-free diet was supplemented with lipid extracts from yellow vegetables (like carrots and yellow corn). Lipid extracts from white corn and white potatoes did not work. These results led to the pigment theory of vitamin A, and biochemists began to search for the magic yellow molecule. In 1920, vitamin A was postulated to be chemically identical to beta-carotene, which is the yellow molecule that accounts for the color of carrots and other orange-yellow vegetables. Beta-carotene is synthesized only by plants and not by humans and animals. We obtain beta-carotene from yellow vegetables we eat in the diet.

The theory that vitamin A was beta-carotene was accepted for 10 years until scientists began to question why cod liver oil, which has no yellow color, was so effective in treating night blindness and corneal ulcers. Was beta-carotene really identical to vitamin A? Like many great scientific theories, the pigment theory turned out to be only half right but in this case, it was half right in the literal sense of the word in that vitamin A is actually half of a beta-carotene molecule. Beta-carotene is not a vitamin per se; it is a provitamin. Let me explain.

The bright yellow beta-carotene molecule of 40 carbon atoms has no physiological action until it is split in half by enzymes in the intestine to produce two colorless molecules of 20 carbon atoms each, one called retinal and the other called retinoic acid. Retinal and retinoic acid are the two active forms of vitamin A that are stored in the liver and used by the body. When we swallow cod liver oil, we are ingesting a mixture of retinal and retinoic acid that were derived from beta-carotene that was originally produced by marine algae, which were then eaten by shrimps, which themselves became the food of small fish, before they became the prey of the larger cod fish, which store the retinal and retinoic acid in their livers.

Retinal is the form of vitamin A that functions in the visual cycle of the retina, and it is the form that prevents night blindness by activating rhodopsin photoreceptors in the retina—a discovery made by George Wald, who was honored with the Lasker Basic Research Award in 1953 and the Nobel Prize in 1957. The other active form of vitamin A, retinoic acid, has a more widespread function in the body and is a hot topic of contemporary research. Several years ago, scientists discovered that retinoic acid activates a family of transcription factors that regulate more than 200 genes involved in the function of epithelial tissues throughout the body. Retinoic acid is the form of vitamin A that prevents dry eyes and corneal ulcerations by maintaining the epithelium of the conjuctiva and the cornea. Retinoic acid also maintains the integrity of the epithelium of the lung and the intestine, which is essential in protecting children against death from infectious diseases. And this is the area of vitamin A deficiency where the epidemiological studies of Al Sommer have been so illuminating.

After graduating from medical school in 1967, Al obtained a master's degree in epidemiology from Johns Hopkins. As an epidemiologist-in-training, he was assigned by the Centers for Disease Control to the Cholera Laboratory in Dhaka, East Pakistan. Here he first became aware of the problem of vitamin A deficiency in children, and he took a keen interest in the topic, especially since he planned to become an ophthalmologist. In 1976, after completing his residency in ophthalmology at Hopkins, Al took off to rural Indonesia where he designed and conducted an epidemiological study of vitamin A deficiency. He and his colleagues examined 4000 children every three months over an 18-month period. The original aim was to determine why some children develop nightblindness and dry eyes while others did not. But he turned up something much more profound and completely unexpected. Children with eye problems due to vitamin A deficiency were dying four to eight times more frequently than children without eye problems. The increased death was a result of respiratory infections and diarrhea, and the risk of death was nicely correlated with the severity of the vitamin A deficiency. Al went on to show in prospective studies that treating children with vitamin A not only saved their eyesight; it also saved their lives, reducing mortality by 30 percent. In subsequent studies in Africa, he also discovered that vitamin A treatment reduced the fatality rate of childhood measles by 50 percent.

Sommer's results seemed too good to be true and were initially greeted with skepticism. It was difficult for the scientific community to accept that a single nutrient vitamin A could be responsible for as much as 30 percent of the deaths of children in the third world, where global malnutrition is rampant. But within an incredibly short period, Al's findings were confirmed by multiple studies throughout the third world, and now the World Health Organization and UNICEF routinely recommend low-dose vitamin A treatment for the prevention of early childhood blindness and death.

According to the landmark 1993 report from the World Bank entitled "Investing in Health," periodic oral vitamin A supplementation is among the most, if not the most, cost-effective interventions in all of medicine. At a cost of only four cents per child per year, the lives of more than a million children are saved each year throughout the third world. This is a wonderful chapter in the history of medicine, and it is also a superb reminder of the dictum that medicine is the tutor of biology. The function of vitamin A in immune defense was not appreciated until Al made the epidemiological connection between vitamin A deficiency and death from infectious diseases. Not bad for an ophthalmologist from Baltimore—or should I say, a visionary ophthalmologist from Baltimore.