For the understanding and demonstration that low-dose vitamin A supplementation in millions of third world children can prevent death from infectious diseases as well as blindness.
Throughout the developing world, in Indonesia and Tanzania, in South Africa and Nepal, in virtually all countries where vitamin A deficiency was once common, millions of children owe their eyesight and their very lives to a visionary, persistent doctor from Baltimore. Alfred Sommer, winner of the 1997 Lasker Award for Clinical Medical Research, discovered that vitamin A, known to prevent blindness from xerophthalmia, also gives children the biochemical strength to recover from life-threatening infections that are common in most of the poorest nations on earth.
Xerophthalmia often begins with night blindness, which in some cultures in called “chicken blindness” because afflicted children mimic chickens’ inability to see at dusk. As xerophthalmia progresses, “Bitot’s spots” appear on the eyes—white, foamy or cheesy accumulation of tissue that is known as a sign of vitamin A deficiency. If vitamin A deficiency progresses untreated, the patients deteriorate and may develop eye ulcers that, as Sommer puts it, “eventually turn the cornea to mush.”
Vitamin A deficiency is one of the oldest recorded medical conditions. The ancient Egyptians treated nightblindness with animal liver (where vitamin A is stored) 3500 years ago. By the early 1900s, the connection between xerophthalmia, overall resistance to infection and vitamin A was well-documented by American and Danish nutritionists who treated their patients with cod liver oil, butter, and whole milk. For all practical purposes, xerophthalmia was erased from the medical map in Europe and North America.
In the developing world, xerophthalmia remained a serious problem whose importance was grossly underappreciated. In Indonesia and Tanzania, in South Africa and Nepal, in places where respiratory and gastrointestinal infections commonly kill children before they are old enough to go to school, xerophthalmia was considered relatively unimportant — except to ophthalmologists. According to Dr. Sommer, “a profound amnesia appears to have settled over the broader context of vitamin A deficiency once it ceased to be a major concern of wealthier nations. Although animal studies and clinical observations had seemingly delineated the wide spectrum of disease associated with vitamin A deficiency, particularly growth retardation and reduced resistance to infection, clinical interest soon fixated on the ocular manifestations.”
After graduating from Harvard Medical School, Dr. Sommer spent time in Bangladesh as part of a medical relief team. It was that experience that later came together academically when he received a degree in epidemiology from Johns Hopkins and then continued through a residency in ophthalmology. In 1976 Dr. Sommer was looking for a chance to return overseas when the opportunity to study xerophthalmia in Indonesia presented itself. Dr. Sommer designed a series of research questions to provide “everything you need to know” to control vitamin A deficiency and prevent blindness. In one of those studies, he and his colleagues examined 4,600 children in rural Indonesia every three months during one and a half years, primarily to determine why some developed xerophthalmia while others did not. Severe xerophthalmia was often associated with excess mortality but that was attributed to the fact that these children, on the verge of blindness, also had other, more obviously life-threatening illness. Now, Dr. Sommer’s combined training in epidemiology and ophthalmology was about to pay off. His study included not only children with signs of xerophthalmia but matched controls with no evidence of xerophthalmia.
As Dr. Sommer sat analyzing his data one night, it suddenly hit him: children with even the mildest xerophthalmia were dying much more frequently than children with normal eyes. Dr. Sommer refers to Pasteur: “Chance favors the prepared mind,” and to Bertrand Russell: “Never let sleeping dogmas lie.” He published his data in a paper in The Lancet 1983. Children with night blindness and/or Bitot’s spots, died on average four times the rate, and in some age groups at eight to 12 times more frequently, than children without xerophthalmia. Furthermore, treating children with vitamin A (2oo,000 I U capsules) for their xerophthalmia, not only saved their sight; it also saved their lives.
“The present study demonstrates that even mild xerophthalmia (eg. vitamin A deficiency) is associated with a marked increase in mortality,” Dr. Sommer wrote in The Lancet. But no one paid much attention. Ordinary vitamin A, at a cost of a few pennies, reduces mortality by as much as 5o%. It seems too good to be true. And, indeed, when Dr. Sommer first presented his data, his colleagues (including specialists in vitamin A and micronutrients) dismissed his work. Profound amnesia.
During the course of his research Dr. Sommer also made a remarkable clinical observation about measles, which in developing countries is a life-threatening infection. Vitamin A, given as acute therapy for two consecutive days to children hospitalized with severe measles, reduces their risk of blindness and their mortality by 5o percent. He’d proved that measles often blinds and kills by its acute, dramatic interference with vitamin A metabolism.
Despite intense skepticism among his peers, Dr. Sommer expanded his studies, conducting randomized trials involving hundreds of villages and tens of thousands of children and he encouraged colleagues in several developing countries to do the same. At one point, when he had to abandon a study in the Philippines because of “civil unrest,” he moved his team to Nepal, where ongoing studies now focus on vitamin A nutrition and the health and survival of impoverished pregnant women.
Today, all of the important players on the world health scene recognize the significance of Dr. Sommer’s acumen as a clinical investigator and epidemiologist. This is patient-based science at its best. Within the decade, another half-dozen significant community-based randomized trials and epidemiological investigations confirmed Dr. Sommer’s data. The physiological importance of vitamin A as a micronutrient is now widely accepted. By 1993, the World Health Organization, UNICEF, and other United Nations organizations had launched campaigns to eliminate vitamin A deficiency. The World Bank concluded that giving children periodic doses of vitamin A is one of the most cost-effective treatments in all of medicine. Furthermore, world health institutions recognize, again on the basis of Dr. Sommer’s controlled vitamin A trials, that giving the vitamin orally is every bit as effective, and a lot more efficient, than giving it by injection — the once favored route of administration.
Because of Dr. Sommer’s persistence and his determination to blend clinical observation with basic science, new work in his laboratory and elsewhere is dedicated to understanding the role of vitamin A in all its biochemical and molecular detail. It is clear, that in the face of even mild vitamin A deficiency the development of the epithelial lining of the respiratory, gastrointestinal, genitourinary tracts fails to develop normally, leaving these crucial organs vulnerable to colonies of bacteria and infection, while failure of normal differentiation of immune cells interferes with a competent immune response.
No less important, Dr. Sommer’s work has encouraged further serious studies by others of the biochemistry, molecular biology and genetics of vitamin A, a molecule that is now known to affect the expression of some 3 oo genes. His work has also stimulated broader enquiry into the existence and clinical significance of seemingly mild deficiency of other micronutrients, such as zinc, iron, and iodine.
For the discovery that vitamin A deficiency, which causes blindness, also causes death from infectious diseases in million of children in the third-world and the demonstration that low-dose vitamin supplementation prevents these devastating consequences, Alfred Sommer is honored with the 1997 Albert Lasker Clinical Medical Research Award.
Award presentation by Joseph Goldstein
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 PhD 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.
Interview with Alfred Sommer and Mary Ellen Avery
Alfred Sommer made his mark on science and human health through insightful studies of 4,600 children at risk of losing sight and life from a diet deficient in vitamin A. Sommer talks about his grandmother, his research, and his luck in this interview with Harvard University Professor of Pediatrics Mary Ellen Avery, taped in September 1997.
Part 1: Destined to become a doctor
Sommer believes the decision to become a doctor was imprinted on his soul at birth by his grandmother. He journeys back in time, recalling key moments of his past and the forces that shaped him.
Avery: Hello, I’m Mary Ellen Avery, Professor of Pediatrics at Harvard Medical School, and have the pleasure this morning of having a conversation with Dean Alfred Sommer of the Johns Hopkins School of Hygiene and Public Health in Baltimore, the winner now being honored today of the 1997 Clinical Medical Lasker Award. This is one of the most prestigious awards in American medicine, and is important in as much as it recognizes every year one or a few people whose work is viewed by their peers, a jury of scientists who identify it as having profound importance on the public’s health. With that, I’d like to turn the conversation over to Dean Sommer, who will, I think, proceed to think about how he became interested in becoming a doctor in the first place.
Sommer: I can never remember a time when I did not want to be a doctor. My becoming a doctor in the first place was very easy. I truly believe that my grandmother, on the day of my birth, imprinted it somehow on my soul and, in fact, I can never remember a time when I did not want to be a doctor.
Avery: Who was this remarkable woman?
Sommer: Well, she was somebody who had been an immigrant to the United States from Eastern Europe, and just thought that physicians were somebody who did good and did well while doing good, and thought that her grandson couldn’t choose a better career for his life—it was never a tussle. Nobody every repeated it. I was never threatened or bludgeoned into doing this, but as I grew up and met physicians as we all encounter our pediatricians and our internists, I couldn’t think of anybody who was having more fun because they were, in fact, respected. They were thoughtful, they were intelligent, they were knowledgeable, and they were helping people.
Avery: Well, you’re all of those things, but did you have any sisters?
Sommer: I had no sisters. I had two brothers, and one of them is a lawyer. He went a different path, and the other one works in business.
Avery: I see. Well, that’s a start, but it had to be sustained against a lot of competing opportunities and interests. Tell us a little more about getting into medical school.
Sommer: Well, medical school is always a challenge but having decided that this, indeed, was what I wanted to do, it was something that I single-mindedly pursued.
Avery: And Harvard didn’t discourage you as an undergraduate.
Sommer: No. Harvard was really very kind and there were lots of people who felt the same way. People were reasonable and collegial, and helped and worked with one another and spurred one another on. Competition isn’t entirely a bad thing, particularly when it’s positive as opposed to negative. And I did, indeed, enjoy tremendously my premedical studies. But I always was interested in history, and if I hadn’t gone into medicine, I would have been a history professor in a small New England college probably. But I’ve maintained my interest in history. I’ve been able to read history on the side, and perhaps that’s given me a broader view than I might otherwise have brought to my academic endeavors. Signing up for the Peace Corps: “one of the few things I did ahead of time in my entire life.”
Avery: I think we could return to that in a little bit. I’d like, though, for the sake of a bit of chronology here, to say now you’ve got an MD degree, what happened next?
Interview with Alfred