1997 Albert Lasker Clinical Medical Research Award

Vitamin A therapy for preventing infections and 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.

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.

Alfred Sommer

Nature Medicine Essay

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?

Sommer: Well, I received my MD degree at the time that Kennedy had been President. We were all, of course, traumatized and we can all remember where we were the day that he was killed, but we had been inspired. I remember his inaugural address as does my wife. "Ask not what your country can do for you, but what you can do for your country." That was inspiring to young people in those days. I remember the formation of the Peace Corps. That was inspiring. And while I was in medical school, someone who became a friend had come back as a physician in the Peace Corps, and we actually signed up for the Peace Corps—one of the few things I did ahead of time in my entire life.

But then as I began my internship and medical residency still in Boston, we got entangled in Vietnam. Given the advice of friends and colleagues and mentors that I would most certainly be drafted out of the Peace Corps to go to Vietnam, we chose instead to accept an offer to go to the Centers for Disease Control and the Epidemic Intelligence Service—which exposed me, just in itself, with an area of medical research and investigation and endeavor that I didn't know very much about. [I] literally fell in love with epidemiology which, in its best sense, is medical detective work. It's Sherlock Holmes played out in the medical arena, and clearly has had and still has the opportunity to impact positively on the lives of literally millions of people at any one time. And that was the beginning.

And then putting together our interest in living and working overseas with being at CDC, the Centers for Disease Control—I hadn't been there more than a month or two when a group of CDC employees who were working in what was then East Pakistan, now Bangladesh, on cholera research and cholera vaccines, came through looking for an additional person to join the group in East Pakistan. We literally jumped at the chance, and then spent the next 2 1/2 years, which were a rather extraordinary social and professional opportunity on our part and experience, and that changed my whole orientation towards medicine and towards the areas of research that I wanted to carry out. Now, as I've told everybody, the two things I really don't like in life are hot, humid conditions and rice.

Avery: Well, this is a marvelous story, but when I think about your excitement about going and living in Bangladesh, I'm not sure everybody would—there aren't many Hilton Hotels there.

Sommer: Well, no, there aren't. I must say that while I was excited and came home and told my wife that here's an opportunity to go over overseas, it means that we had to sign up for next year so we were there for 2 1/2 years. I then looked up where East Pakistan was. That didn't seem to be too bad. And then I looked up in the back of the National Geographic Atlas—they always list the humidity and the temperature—and it was 120 degrees, it seemed to me, on average in the shade, and 100 percent humidity. And I said, "hmm, maybe this isn't where we want to go." But, no, we really do want to go, and we did go, and we had a marvelous time. There's a whole group—

Avery: How did you keep your cool?

Sommer: Well, when you're out in the field, as I spent a fair amount of my time, you do adjust. Now, as I've told everybody, the two things I really don't like in life are hot, humid conditions and rice. And here I went to a place that was hot, humid and the only thing to eat was rice. Well, you learn to like rice and you learn to live in hot, humid conditions. But where we lived in Daka, where our home was, we actually had air conditioning. You come into contact with marvelous people. Marvelous people locally who are very much committed to moving a country forward and marvelous people who have gathered from around the world in order to work in places like this.

Avery: Just as a little aside, do you adjust physiologically in time?

Sommer: Oh, I think you adjust mentally in time.

Avery: I see.

Sommer: I don't think I sweat any less than I would have in Baltimore.

Avery: Well, this is fascinating and I wish sometime this audience might have a chance to hear your wife's point of view. But so be it. Let's move on because you're now poised with superb education, you're committed to the Third World. Is that the right word for it?

Sommer: Yeah, Third World is politically correct. I have lived most of my career by doing whatever seemed most interesting at that particular moment.

Avery: Or the nonindustrialized world. Fill in the gap between that and your getting involved in actually doing sustained research and to the vitamin A story.

Sommer: Well, I ought to provide a disclaimer at the beginning. Some people are far more directed and deliberate than I am, and I have lived most of my career by doing whatever seemed most interesting at that particular moment. So I have not said, gee, I've got to do this now and then following that I ought to do this because that'll best position me for the future. So I had actually decided before we went to CDC that I would move from internal medicine to ophthalmology, just because at the time it seemed to me there was much more opportunity...and the academics via ophthalmology, where there were very, very few full-time academicians back then, where there were already many people working in academics in internal medicine.

And then I went overseas and had this marvelous experience working in the field, and literally having millions of peoples' welfare and lives hinging upon decisions that I made and investigations that I carried out. I found that extraordinarily exhilarating that the amount of leverage, the amount of impact I could have was so much greater than I could on a one-to-one patient-physician basis. As fulfilling as that is in its own right, I made then the commitment to public health and public health research, an area where I knew that I was going to enjoy myself.

I then came back to the United States and was supposed to begin my training in ophthalmology, but decided that since I had been doing epidemiology for three years, I really ought to learn something about it. And so I again postponed my residency training for an additional year in order to pursue a master's degree in epidemiology at the Johns Hopkins School of Hygiene and Public Health. Following that, I entered my eye residency at the Wilmer Institute at Hopkins. And that, indeed, made a whole difference, because I came to ophthalmology with a whole different perspective in which I would think about populations of people and populations of eyes much more so than the one specific individual with all the variation you see with one individual. I could think of it as a distribution in populations. Variation is a thing that happens in biology; then how do you understand what's moving something in one direction or another and isn't just a chance event?

Part 2: The right place at the right time
Preparation and luck lead to the discovery of the vitamin A deficiency disease. Sommer credits Doctor Susan Pettis, Director of Blindness Prevention, for advancing his career. Sommer also describes fundraising for the project.

Avery: And how did you latch onto xerophthalmia, the vitamin A deficiency disease?

Sommer: Again, so many things in life are luck. Or as my favorite saying of Pasteur's, "Chance favors the prepared mind." There was a remarkable woman, still around today, Dr. Susan Pettis, who is a social worker and she became -- she actually received her doctoral degree when she was well into her 50s, having decided after a long career to go back to school to get a masters degree, and then hanging around to get a doctoral degree. And she became the Director of Blindness Prevention for a very old, American agency then called the American Foundation for Overseas Blind. It had been set up following World War I to assist the war blinded in France specifically, and in Europe more generally—but was looking actually to broaden its work, to work in a developing world and to begin to prevent blindness as much as to take care of, educate and rehabilitate people who were blind. And it's always remarkable to me to think that they hired Dr. Pettis. It's humbling because I wouldn't have. Here was someone who knew nothing about ophthalmology.

Avery: Now, who were they?

Sommer: They would be the Board of Directors of this agency, the American Foundation of Overseas Blind. He said to Dr. Pettis, "you ought to meet this young whippersnapper who has just come back from overseas..."

Avery: But how did you meet her?

Sommer: They made a decision that nutritional blindness—since that was a cause of blindness in children and people understood that this might be a serious problem in developing countries—that that was the area they were going to focus on. Well, it turned out, through these usual complex webs of causation, that an old friend of hers from Mobile, Alabama—where they both grew up—was then the Professor and Chairman of Ophthalmology at the Wilmer Institute and had been very supportive to me by allowing me to continually put off my residency training to pursue these rather esoteric interests in the Third World and epidemiology, but understood. He's one of the few people who understood that this might be a niche that would be very useful to have somebody pursue. He was supportive, she came to him, asked him to be on our Advisory Board, said that she was looking for someone to do something about developing countries and nutritional deficiencies.

Avery: Let me interject—he was Professor and Chair of Ophthalmology at Johns Hopkins at the time.

Sommer: Johns Hopkins, right.

Avery: And you were the young fellow --

Sommer: I was the young fellow who hadn't even been trained in ophthalmology yet.

Avery: Alright. Got it.

Sommer: I'd even had a beard for a while, which was really not on at Johns Hopkins in those days. And he introduced us. He said to Dr. Pettis, "You ought to meet this young whippersnapper who has just come back from overseas and seems to be interested in those things," and that was in early 1973, January or February. It happened to be that her primary interest then was work that they had been asked to do in the new country of Bangladesh, which was the country that I had just left. So things have a way of working out together. Then I worked with them, providing them with advice and flying overseas and evaluating issues and helping to design programs while I was spending my three years as a Wilmer resident at Hopkins, learning ophthalmology.

And all along, I would keep saying, "You don't know enough about the issue to be able to develop and design an effective program." There were more things we needed to learn. So then we jumped to the next event, and that was while I was a resident in 1974. There was the first International Conference to discuss nutritional blindness, and that was in Indonesia. I was not to be invited because the work that had been done had been done in Central and South America, and quite appropriately, they wanted to invite people from those countries. But Dr. Pettis convinced them that while they certainly should do that, they should invite me because I really had an insight and understanding and perspective that was different than most people. Friends who live in Indonesia said you'll never be invited to Indonesia. You talk too much.

On my part, I was looking to find an opportunity to go back overseas again. Our family had enjoyed our stay and before our children became too much older, we thought we'd want to have that experience again. So I went and attended this meeting. I spoke more than I probably should have so friends who live in Indonesia said you'll never be invited to Indonesia. You talk too much. And I said but I can't -- that's the way I am. I said, well, not a chance. And the last day of this meeting, I was sitting on one side of Dr. Pettis and the high ranking member of the Ministry of Health of Indonesia was sitting on the other side, and I happened to be mentioning to Susan I thought this would be a wonderful country to work in. The people seem marvelous, they had this very big problem of nutritional blindness, but I had no idea how I ought to pursue that.

Avery: Now wait a minute. Did he know that it was vitamin A?

Sommer: Well, we knew that vitamin A deficiency was the primary cause of this very specific classical presentation.

Avery: Of xerophthalmia.

Sommer: Of xerophthalmia. Not of all nutritional blindness, not of measles-related blindness, though it turns out that it was important for that as well. On the other side of Dr. Pettis is this gentleman from the Ministry of Health, who is whispering to her, "Is there any way that we can get Dr. Sommer to come here for a few years and work with us?" And she's sitting in the center and smiling to herself, and saying I think I can make a deal here.

Avery: Is she the one that had the resources to fund this?

Sommer: She didn't have the resources to fund it, but she had the get up and go to work with me to seek those sources. And in 1975, when I had two months off from my residency, my family and I went back to Indonesia and did the field work and met the people that I needed in order to write up a detailed research plan, with which we were then able to go out and raise funding.

Avery: From where?

Sommer: Primarily from our United States Agency for International Development, our Foreign Assistance Program. And for reasons that I can't tell you today—other than one very insightful man, Marty Foreman, who was in those days the Director of the Office of Nutrition at USAID—he truly believes in the potential importance of vitamin A and the issue of nutritional blindness, and he came through despite the advice of an outside committee to fund this research project that we needed to undertake.

Avery: That deserves a comment or two. You could have been easily discouraged because this was the kind of research that you would write up for an NIH grant, for example. But AID has a long history of supporting work around the world and yet, I think some people wonder if it isn't politicized a good bit. Who determines in the staff of AID where their considerable resources are to go year by year?

Sommer: Well, I think it's determined at the first level in a broad, strategic sense by the Administrator, the person who directs the entire Agency for International Development. But that person is obviously acting in good faith based upon competing recommendations that are brought to him or her from the staff in the various areas in which AID is active. So a lot of their work is in the agricultural arena, a lot of their work is in providing food, a lot of their work is in infrastructural development—but they do have a significant presence in the area of health, nutrition and population. We spend far less as a percent of our wealth than any other developed country in foreign assistance, and it's less than 1 percent of our GNP.

Avery: Now, tell me, they must get their funding ultimately from the Congress of the United States.

Sommer: They get their funding ultimately from the taxes we pay.

Avery: So have political interests worked to help or hinder this in recent years?

Sommer: Well, not this area of research or endeavor specifically, but certainly generally, politics has worked against our Agency for International Development and, therefore, our standing in the developing world. You have to realize, when you live overseas—and we've lived overseas a considerable number of years and through natural disasters, through civil wars and what have you, people, no matter where they are—the common person looks to the United States as a fount of democracy, of doing the right, of supporting the right causes. And I must say, sometimes it's been very embarrassing to us that we haven't been able to be there when we should be there.

And when you look at how much we actually put in, the public is confused but supportive. If you ask the public, as the Harris Pole does regularly, is the money we spend overseas a good thing to do? They will say yes. Invariably. And they will tick off the areas that are important. If you ask them how much money do we spend overseas, they will say 5 percent to 15 percent of our national GNP. And then they say but maybe that's too much. Well, in fact, we spend far less as a percent of our wealth than any other developed country in foreign assistance, and it's less than 1 percent of our GNP.

Avery: On the other hand, it's in dollars probably, we're up there.

Sommer: In dollars, it is large. We're almost as large as any other place because we have such a huge economy, but as a percentage, it doesn't begin to compare with Holland or the Scandinavian countries or Belgium or the U.K..

Avery: But it is, in a sense, wedded to political purposes, at least to the best interest of the United States in some senses because there are needs all over the globe. Why do we choose one or another? Indonesia ranked up there, I guess, on the find of whoever your Administrator was and all I can say is, thank God.

Sommer: Right. It certainly worked out well for us. They said, well, this is not ideal for your career... And I said well, I'll take that chance.

Avery: Now, let's go on and see how it worked out well.

Sommer: Well, having finished my residency, again one makes a decision. People were very supportive as they always have been during my career and tried to encourage me to stay back at Hopkins and join the faculty at that point. I said no, I have this wonderful opportunity to go overseas, work with people in another culture. I have something to contribute, and [there are] intrinsically a very interesting series of questions that need to be answered. And they said, well, this is not ideal for your career. You ought to stay here. You're doing epidemiology of ophthalmic diseases. Nobody else is doing it. You're establishing the field and people will forget you in three years. And I said well, I'll take that chance. This is an area that seems interesting to me and I'm going to take that chance. And certainly, the history of it all, the way it played out is I made a much bigger impact taking this chance than had I tried to be very careful and conservative of the way I approached my academic career.

Avery: We understand that applies to almost everybody who does something innovative in research. As somebody said, if you knew what the answer was, you never should do the experiment.

Part 3: A daunting task
Sommer finally gets to Indonesia, and the work begins. Driven by compassion and curiosity, he spends three years working with sick children before returning to the States. He describes the research process as "peeling back the layers of an onion."

Avery: But let's go ahead. Let's get you into Indonesia with your family and you've done the field work. What do you do next?

Sommer: Well, in our case, again, we had a wonderful opportunity. I had an additional year of funding because we knew we would spend up to the last day in Indonesia, those three years, collecting data. There was no time to sort through it, clean it up, think about it, write it up, publish it. So we spent that fourth year in London, where I was fortunate enough to have been provided an office and an opportunity to do some teaching, but mostly to spend time thinking and working and writing at the Institute of Ophthalmology in Judge Street, the University of London. And during that time, my primary concern had been to go through those areas of our studies that seemed the most immediately relevant and important, which means it's not where you necessarily find particularly important insight, because now we're tracking through research that we had anticipated what the results might be.

Avery: I want to interrupt a minute here to see. I haven't quite got in my head whether you go out to one village and look at everybody in a village.

Sommer: Oh, okay.

Avery: Where do you get the denominator that you have to have for this kind of work?

Sommer: Well, it depends on the studies. There are three very large integrated studies. One series of studies, in which we had to do some very sophisticated clinical and biochemical analyses, were all done on children who came to the hospital where I had my headquarters in Indonesia, in Bandung, Indonesia. So those were where we could collect samples, take photographs of the eyes, take blood specimens for looking at metabolism and the biochemistry of what was going on.

Avery: So your first denominator was sick children.

Sommer: First denominator was sick children. And in the case of children who were going blind, there were about 350 such children. And in those who had milder lesions, but might well have gone blind had they been left alone, it was probably in the order of a thousand children.

Avery: Over --

Sommer: But these were children who came to us over three years.

Avery: Three years.

Sommer: And in these children, we were able to do a number of things because it was a very tightly controlled environment and we could randomize children to the different types of treatments. And probably the most practical important thing that we were able to demonstrate was that using a very inexpensive, oral dose of vitamin A, we could stop and reverse most of the damage that had preceded their going totally blind. If the eye had been totally destroyed, there was nothing that we could do at that point—though we could, again, through using an oral dose of vitamin A, save the other eye if the other eye was not fully destroyed yet. And the practical implication of that was clear. That means that for two or three cents, anybody anywhere in the rural area, which is where most of these children would come from, could treat nutritional blindness and prevent it as effectively as anywhere else or anyone else.

Avery: Two or three cents for the medicine, but the delivery around the world is another story.

Sommer: Well, if you're going to prevent it, that's another story. But if a child came to a health worker usually with only one year of training out of high school and the mother said this child can't see after dark, they didn't have to go and take a four-day trip to get to a hospital to use what up until then had been the recommended therapy—which was a much more expensive injection that required a needle and a syringe, and these generally are not clean in developing countries. So they run the risk of getting hepatitis and in these days, AIDS and other infections. This was not an enormously intellectual exercise. It was just a rigorously conducted medical trial.

Avery: But an enormously important one.

Sommer: But from a practical perspective—so that was the type of analyses that we did at the beginning.

Then we had two other major studies. One of these was to gauge the magnitude of the problem and the factors that contribute to it around Indonesia. There, the denominator was 35,000 children, and these represented a random sample of children throughout Indonesia, or at least throughout the six largest highlands.

Avery: You weren't, then, thinking of regional differences and customs or diets or anything?

Sommer: That's what we were looking for. We were looking for where in the country was the problem the most severe and what were some of the factors that might be responsible for it.

And in the third study, and what perhaps turned out to be the most important fact, was one in which we chose a rural area two hours away from our headquarters, and that area had been chosen because our preliminary study of clinic records suggested that xerophthalmia and nutritional blindness were particularly prevalent and common in that region. And there we studied 4,000 children in these rural villages and re-examined them every three months for 18 months. A pediatrician examined them, an ophthalmologist examined them, a nutritionist took a dietary history, we took blood samples on a few of the children periodically in order to better understand why some children develop vitamin A deficiency and nutritional blindness while other children didn't. There's always another mystery...another medical detective story.

Avery: Let me comment here. Once you had your hospitalized children getting better with your oral tablets of vitamin A, you could have said look what we've done. You could have packed your family home, you could have gone around and said we know how to stamp out night blindness in children. You didn't do that. You asked the next question. Why some children, not other children? Are there regional differences, customs I suppose you were thinking about. But still more than that, you weren't just an ophthalmologist at that point, you were the internist you started out to be because there were physical exams, you said, and diet history, the whole ball of wax.

Sommer: The whole ball of wax. That's absolutely right.

Avery: And that, to me, is remarkable. Very few people stick with something in a situation that wasn't easy to work—for sure, are driven by curiosity.

Sommer: Driven by curiosity. You know, as you peel back the layers of the onion one at a time, there's always another mystery behind it, another medical detective story.

Avery: You wanted that answer then. You didn't want to go home and come back ten years later with an army of investigators.

Sommer: Absolutely. Well, we did do that, too, subsequently. But that's because we kept peeling back the onion and finding more and more of interest and, of course, the ultimate goal of any medical intervention is to prevent people from getting disease in the first place. Not going out and trying to close the barn door after the horse is out.

Avery: And there's your public health interest.

Sommer: Right. Going through these massive printouts...I had this "holy cow" experience.

Avery: Okay, go ahead.

Sommer: Well, so I did the more obvious and immediate things that I had been thinking of, those experiments where if it comes out the way you expect, you haven't learned anything.

Avery: Yes.

Sommer: But sometimes they don't come out the way you expect, and that's when you learn something.

Avery: Well, let's hear about that.

Sommer: And that was two years later. I was now back in the States, at Johns Hopkins being your full-service professor of ophthalmology, seeing patients, doing surgery half a day a week, but still conducting both research that was important to people here in the United States on glaucoma as well as my international interests in vitamin A deficiency. One relatively quiet week, the week between Christmas and New Year's in 1982, I was going back, peeling back the next layer of the onion, as it were, looking at the data from that study where we re-examined children in the field every three months to determine what was different about the children who developed vitamin A deficiency and those who didn't. And as we had anticipated, children who had respiratory disease a month ago were more likely to become vitamin A deficient. Children who had diarrhea were more likely to become vitamin A deficient. Children who had a diet that was poor in vitamin A or provitamin A carotenoids were more likely to become deficient.

But as I was going through these massive printouts, very simple minded, 4 x 4 tables tracing the children from one exam to the next examination, I had this holy cow experience or epiphany where it suddenly became apparent that children who had had these mild, early eye signs of vitamin A deficiency—night blindness, for example—at one round didn't seem to be around in great numbers than the next round, three months later. I said, gosh, what in the world is going on here? So with my little hand calculator, without the computer, and just sitting there with these piles of printouts, I started to do a rough analysis of a different question. And that question was: do children who have vitamin A deficiency die more commonly than children who don't have obvious signs of vitamin A deficiency? And there it was. Children with the very mildest manifestations of xerophthalmia died at three times the rate of children that had normal looking eyes and had no complaints of night blindness. Children with a little bit more severe deficiency died at six times the rate. Children with more severe deficiency, but still not anything that was approaching a threat to eyesight, died at nine times the rate of children with normal eyes.

Avery: Now how were you diagnosing night blindness at this point?

Sommer: The night blindness at this point was a mother's history because we had already shown early in our work in Indonesia that a mother's history that her child could not see at dusk or dawn, could not find their food, would huddle in the corner of a hut, not walk around the village—she was as accurate or more accurate than our objective tests. And the reason we know is that if we compared our objective tests with what she said with the serum vitamin A levels of the children, her history had a better correlation with the serum vitamin A levels than our objective test had. So in this population, we were able to know precisely what a child was getting simply by asking the mother. Total surprise. Absolutely. We had not anticipated this at all...

Avery: That's incredible. And all of this sort of analysis which you were doing led to what was a complete surprise.

Sommer: Total surprise. Absolutely. We had not anticipated this at all and we wrote this up and published it inThe Lancet at the same time that we took a new study we were about to carry out in another area of Indonesia, 1,200 miles away from these observations. We were doing a randomized trial of giving one, three cent, large dose of vitamin A to half the children every six months and the other group not in order to determine whether—we originally set out to determine whether, in fact, we could prevent nutritional blindness, and we fully expected that we would be able to with this regimen. And we now, before we actually launched the study, made the primary outcome of interest whether, in fact, we impacted on children's health and survival. And that study included over 20,000 children in a remote area of northern Sumatra. Two years later, we had the answer that those children who had been assigned to receive vitamin A had 35 percent fewer deaths than the children who were not assigned to receive vitamin A.

Avery: And cause of death?

Sommer: Well, in that first study, we didn't know because we did not have the time and did not have the advanced warnings as we had just made this observation and turned to study into it to actually set up a sophisticated monitoring system to try and determine why a child died. That is even difficult to do even now, though we have much, much better data because if a child dies in a remote area, it takes a week or two for you to find out. You then send a trained field worker or physician to the area and then ask parents why a child has died. You ask the standard questions, did they have a fever, were they sweating, were they having difficulty breathing, did they have diarrhea, did they have measles? Other than things like measles and diarrhea, which are very easy for parents to diagnose, other things are much more difficult.

Avery: Measles is easy for parents to diagnose?

Sommer: Because the child has a fever and a rash and everybody recognizes measles.

Avery: Everybody knows it because it's so common.

Sommer: Right. Because every child gets it eventually. But in the subsequent studies that we carried out, in those, we set up these intensive monitoring systems, and it was quite clear what was happening: children who were receiving this vitamin A every three months or every four months or every six months, depending upon the way the study was designed, they were much less likely to suffer severe, life-threatening infectious diseases. Nobody is going to fake death because they received the placebo.

Avery: Was there a placebo control at this point?

Sommer: In the first study, there was no placebo control because the government was uncomfortable with doing that. Now, let me tell you the implications. I didn't have difficulty with that because placebos, for the most part, counter the potential for subjective bias, where the patient feels better because they've gotten the medicine.

Avery: That's what I'm wondering.

Sommer: But in this instance, death is a pretty hard end point and nobody is going to fake death because they received the placebo. They didn't receive those placebos so, to me, it did not detract from the rigor of the study. But, I must tell you that from a political point of view, many scientists and certainly all policy-makers who had to make decisions whether they were going to use and divert some of their limited resources to controlling vitamin A deficiency made a big thing about the lack of a placebo, and said they didn't believe the results of this study because it did not have a placebo control. And that charge against that study probably delayed by two or three years our ability to convince policy-makers around the world that this was a valid observation, that they could do something that was cost-effective to reduce child mortality.

Avery: Extraordinary. But let's move on. There had to be a step that made the nonbelievers believers. What was that?

Sommer: Well, that's multiple steps and that basically was to go out and continue to collect data in studies that were increasingly refined.

Number two, to encourage many other scientists, independent of us, to undertake these studies. And since very few people had ever done these kinds of studies in large groups of children in developing countries, it meant assisting people, helping to find money for other people to do these studies, and we did all of those things.

And then we played a major role in organizing an International Vitamin A Meeting of the International Vitamin A Consultative Group, which meets every 18 months and brings together scientists and policy-makers to share information, to share their latest thoughts and studies so that those things that we learn from the field, that we learn from our research, and that we feel comfortable and confident about, can be converted as quickly as possible into official recommendations. WHO, the World Health Organization, and UNICEF were regular colleagues in these international meetings and in the advisory committees that were set up, and they would usually be set up under the auspices of WHO because that has a great imprimatur.

Part 4: Helping hands
Creating a cure required support from other colleagues, organizations and individuals. Sommer talks about UNICEF chief Jim Grant's contributions. Without his help, Sommer's work could have been delayed interminably.

Avery: I gather that in that era, James Grant would have been key.

Sommer: James Grant was a key supporter from the very beginning.

Avery: When did he get on board?

Sommer: Jim got on board about 1986. I first went and told him the story following the first observational study in 1983. And then once a year, I started to update him and by 1986, the annual publication of UNICEF, "The State of the World's Children," they published their first full article on vitamin A deficiency and what this might mean. They came back to the story again in 1988, by which time Jim Grant was carrying around a pocket full of vitamin A capsules whenever he traveled overseas. And you know, he always had this way, here's the ORT solution and here's your vitamin A capsule and by George, Minister of Health and Mrs. President of the country and Prime Minister, this is what you have to do to help children. Jim Grant (was) getting the message out before the scientific community was ready to accept it.

Avery: Let me comment a bit that I was a great admirer of Jim Grant and traveled with him sometimes to various places such as Cuba, and I asked him how he could possibly have been so effective; he gave me the formula in this sense. You can't do anything without getting the head of the country or the Minister of Health to bless it because most countries in the world are dictatorships and people are scared if the boss doesn't approve, I'm in trouble. And so, the way in which he got permission to immunize children against polio in Latin America was to go see the Pope, because the Pope was the most influential fellow in Latin America. And remember his instructions were, he asked the Pope to ask all the priests in Latin America when a child was brought in to be baptized, the priest had to ask was the child immunized. And with that authority, polio has been wiped out of the Western Hemisphere.

Sommer: Absolutely.

Avery: So that was one step. The next step was that he—or next comment about Jim Grant was he was always ahead of the times. Oral rehydration therapy wouldn't have gone anywhere if he hadn't been convinced that it worked. And now you've given me a third example. Without Jim Grant, this could have been delayed a long time.

Sommer: It certainly would have. Actually, the first time this came to public attention was when Jim was out visiting Ethiopia and the Sudan during the starvation of 1985, and he had heard on the flight over from somebody who knew about my work about the vitamin A issue. He immediately wired back to UNICEF to get some of these capsules and have them flown out to him. And when he would hold his daily press conferences as he went from relief camp to relief camp, he'd pull out these capsules and Newsweek, I recall, having a picture we all saw in those days of a child near death, severely malnourished, what have you in the refugee camps on the cover of Newsweek.

And then there was a regular article in Newsweek and a side bar, and the side bar was entitled "Golden Bullets Save Lives." That was Jim Grant getting the message out before the scientific community was ready to accept it. And he followed it right up until then. In 1990, he made vitamin A deficiency eradication one of the seminal goals of the Summit for the World's Children. So it became part of the Declaration of the Rights of Children, and for a few years, at least once a week, he would call me usually in the middle of the night or my fax machine at home would dingle, dingle at three in the morning, and I knew that that was Jim Grant. I would always get up because I knew that he was in his office at UNICEF Headquarters at three in the morning, and if he was sending me a fax at three in the morning, the least I could do is get up and respond. I would invariably call him, and then we would settle whatever the issue was that he was concerned about.

Avery: Well, now, I'd like to summarize this by putting it in the perspective of the issues here that I find seminal. One was, first of all, your unique training in epidemiology and your commitment to public health as well as your skill as a clinical ophthalmologist. Perseverance is the key but curiosity is also another key. But the point you just made, I think, is terribly important for all research. One is the importance of a surprise. And when John Enders, a Nobel Laureate for having made the polio vaccine possible, was dedicating our new Enders Research Building at Children's Hospital, Boston, I'll never forget his comment. "May this be your mansion of many surprises."

And the final point with Jim Grant, the Chief of UNICEF for many years, as an advocate, these studies came into perspective and were appreciated around the world through the mechanism of international conferences in part, but largely because of the advocacy of one man who, in my view, made history by understanding more than anybody I've ever known, what the important issues were and with his own enthusiasm mobilizing people to carry them out.

Without an advocate, a lot of research goes down the tubes. The Lasker Foundation, who has made this interview possible, I think is plying this very important rule in American medical life by sponsoring these high profile awards. Because in doing so, they are saying this is important and that can accelerate the further work that needs to be done. The world's a big place and there's a lot that needs to be done, not only in terms of making these findings applicable to all children, but more than that, stimulating now the very basic science which is telling us about the role of vitamin A and the immune function—and perhaps in cell growth and differentiation in this form, with the chemical name of retinal. This is a great story of clinical research changing the fate of millions of children around the world.

Thank you, Al Sommer.