Founder Stories: Roy Vagelos, Biotech legend & former CEO of Merck

My upbringing was kind of unusual. I was born into an immigrant Greek immigrant family living in New Jersey, so my first language was Greek. As I grew up, I was not at all interested in education because I was more interested in fooling around. Only as I approached high school did I start hearing the drumbeat from my parents, especially my dad, who felt that higher education was important if I was not going to be in the family business, which he did not want me to be, which was a small restaurant or luncheonette. So he was very anxious that I be educated so I would get into some other profession. His dad was a physician trained at the University of Athens in Greece but then living on a small island in Asia Minor, which is where my dad and mother were both born and raised. They immigrated, my dad immigrated first, and my mother followed later because he went back to an arranged marriage, and they came back together and then they had a family of three. I grew up in North Jersey, went to high school in Rahway, New Jersey, and of course Rahway was at that time the headquarters of Merck, and most importantly the location of their major research laboratory. We had a small restaurant in Rahway, and our major customers were Merck people. So as a soda jerk, dishwasher, whatever in a small luncheonette, I heard all the time about Merck and specifically what was going on in research from scientists and engineers. They were terrific people, they had great ideas, they loved what they were doing, they were passionate about their work, and I was infected by that. So when it came time for college, I spoke with a number of them and they suggested I go into chemistry. I was by that time doing well at school, actually I did very well in high school, and went to the University of Pennsylvania where I majored in chemistry. So that was really the start of my career and the basis of my entire career, because everything I did after that was anchored in chemistry, and all the research I did, whether it be basic research which I did at NIH and at Washington University School of Medicine later, was biochemistry. So that's how it all started.

That almost happened then. I was finishing my second year at the university, and I met with an advisor for the first time actually, and he pointed out that because I had taken so many courses in science and a lot of labs, I had many credits and could actually graduate in the next year if I took a couple of courses in the summer. Because I was a scholarship student and was rather concerned about expenditures at the time, I took them up on that and agreed to take a couple of courses in the summer. But then suddenly I needed to decide whether I was going to do chemistry, which had been my idea in going to college. I thought about it, and then it became apparent that my background, my granddad was a physician, he must have been interested in what was going on in science, whatever science was known in the late 1880s. At the last minute, I decided I would go to medical school. Having done that, I realized I had no background for it; I had taken no biology courses. So I took my third year at Penn and took a couple of biology courses, just sneaked through, and I went to medical school on that basis. I went to medical school with the idea that chemistry would be useful in understanding what was happening in medicine, both in understanding human biology and whatever was known about drugs.

Yes, yeah, it was amazing. Now I take you back to 1950, and I shifted from the University of Pennsylvania where I was an undergrad to Columbia, mostly to change cities, there was no major reason for that. I was initially concerned and had some difficulty because I have essentially no memory. I knew that for years because I could never memorize lines of poetry or anything else, so I function largely by feeling my way through things and understanding, but no memory. The first course you're exposed to is human anatomy in medical school, and I almost dropped out because I just could not do it. I went home at Christmas and considered not returning, but I returned and finished, but had a tough time with the memory courses. Then as we got into biochemistry and the other things, I finally got with it and was able to especially get turned on when I met with patients. The patient care part of me was very much turned on at Columbia University, and I loved working with patients, and I thought that that would definitely be my career, even though I did not use chemistry at that point because there was very little chemistry that was used to understand even the drugs and how they worked. So I shifted and became a convert to patient care, which was magnified when I went to the Mass General Hospital as an intern in Internal Medicine. That was a great experience because again, shifting from New York to Boston and Columbia to Harvard gave me a new view of the way things are done. I must say I recommend that to students now. I found the practice of medicine, which of course we're practicing the same medicine, was done in a much more individualistic way. There was no rote way of treating a patient with diabetic acidosis; different people followed different ways, they thought their way through, which fit my style anyway. I loved being at the Mass General Hospital. That turned out to be again a turn-on in patient care. So by the end of my two years, which I had to stop because of my having been deferred for the doctor's draft, by the end of two years I was absolutely sure that what I wanted to do was internal medicine and cardiology. I had become interested in cardiology, so that was again a focus on patient care.

Absolutely. I actually signed up for the Army, I was following what I was told to do. Then I was called by a friend who had gone to the NIH from the Mass General Hospital, and he called and said, 'Why don't you come and visit?' First of all, I'd never been in a plane and I had very little money, but by then I was married and my wife was making, I think, three thousand dollars a year, which was enough to support us. It's hard to believe, but that is the case. So I flew to Washington, spent two days I think, and visited largely the National Heart Institute, the name was different at that time, of course it was only one organ. I met Earl Stadtman, who was one of the probably two best known biochemists at NIH at that time, and I had been steered to him by Paul Zamecnik, who was a biochemist MD at the Mass General Hospital. When I met Earl, the deal was that I would at the National Heart Institute, to make up my two years of time for the government, I would spend half time taking care of patients and the other half time I would be able to do research, any kind of research, clinical research, basic research, whatever.

Exactly. So meeting Earl was quite an experience. He was very soft-spoken, his PhD had done his PhD at Berkeley with a very famous biochemist. He talked about his research. Now I had last taken biochemistry in my freshman year at Columbia, so it was quite a while, it was five years prior to that, and biochemistry was mushrooming at that point. Earl was very soft-spoken, but as he spoke he became very excited about his work, and his excitement caused me to get excited even though I didn't really follow what he was saying. He was clearly working in areas that I'd heard about, knew a little about the beginning, but I didn't follow exactly where he was going. So I asked him a lot of questions, and by the end of that time I said, 'Look, I'd like to work in your lab.' He looked at me and said, 'You know, I've never worked with an MD.' I said, 'Well, I have never worked with a PhD, so why don't we give it a trial?' He said fine.

Yeah, well, that was an interesting experience which I tried to forget. The incident was my coming in after a weekend in the National Heart Institute, where my job was to take over the patients who had been admitted to the National Heart Institute over the weekend. This was Monday morning, and I walked in. You have to remember that I'm a proud graduate of the Mass General Hospital, thinking I was pretty well trained at that point. I was handed a patient where I was told that the patient came in, a man who was having a major problem with seizures, pain in the chest. He was admitted with the idea that probable some problem with his heart or potentially his nervous system, his brain, because he was having these major seizures and chest pain. So I examined the patient and could not figure out what he had, but because I didn't find anything wrong with his heart and I didn't see anything in his lab work that would suggest what the diagnosis was, I wrote a note immediately after seeing the patient that as far as I could tell the heart was okay and everything I saw in his study of his head was also normal. But I was insecure, so I asked for a consultation by one of the top neurologists in the National Institute of Neurological Diseases and Blindness. Sure enough, the top clinical guy in the institute came to visit with an entourage of people and examined the patient, looked at the X-ray of skull, and pointed out that there was a problem there. I looked and I did not see what he was pointing to. So he then looked at the chart and looked at my note and said, 'You know, whoever wrote this note, it's not very good,' made some derogatory remarks which really floored me because I hadn't been used to that kind of treatment at the Mass General Hospital. When he left, he felt that this man had a neurological problem as seen in the skull films. When he left, I wrote a note, I typed a note to him saying that I thought he was inappropriate in the way he had reacted to my examination of the patient, in my opinion, and I said some other things I should not have said which were very unfortunate. But I was pretty much angered by this interaction, and so I determined to figure out what this patient had. I was sure he didn't have heart disease because I was pretty good at that, I couldn't be sure about the other. But the significant thing, he was having grand mal seizures, what looked like grand mal seizures. He would bite his tongue in the evening and pee in the bed, and he said he had pain, and the nurses would come to him and he said he needed morphine because that's what he was used to, they would deliver the morphine. So I set up to watch this. I sat up in the doctor's quarters but right opposite, I was sitting actually in the nurses' area, in a place where I could watch through a crack, the door was left open just a little bit so I could watch him during the night. I noted that he would, well into the evening, start having his so-called seizures, writhing in the bed and peeing in the bed and biting his tongue and asking for morphine. So as I saw that for a couple of evenings, I made some calls to the city hospitals to see if anybody else had seen this guy. Sure enough, he was a known figure in the city hospital system, and they said, 'Oh, you've got Charlie up there?' I said, 'Charlie?' Yeah, and they said, 'Oh yeah, he's you know, he does this kind of thing.' So I confronted him and said, 'Look, I know you're faking.' I offered him some money to take a cab, and he got out of bed and took a cab and went away. This neurologist had gone to the head of the National Heart Institute asking that I be court-martialed. Instead, I had a presentation to the clinical staff of Munchausen's syndrome, which is these patients who pretend that they have some kind of medical problem in order to get something out of it, usually drugs at that era. So he disappeared, and I learned definitely not to write notes of that sort. But it was an experience that I was happy to get by. I was not court-martialed. In fact, I stayed at the National Institutes of Health instead of two years, I stayed for a long time.

It was a very interesting experience because Monod was a person who had dreams in science, and he was very broad, and would take laboratory observations, research observations, and expand them into whole scenes. I wasn't used to that. So we worked together, and I learned again as almost as an apprentice from Jacques Monod, microbial genetics. All the time I was in the lab, I was interacting with people who were developing essentially molecular biology, and he was expounding talking about the potential of understanding how genes are translated into proteins. That was great, it was very exciting, and we had a wonderful time. But although I learned the microbial genetics, I was very anxious to get back to what I was doing because we were on the verge of understanding fatty acid biosynthesis, and the work in my own lab to me was equally exciting and actually more exciting because things were about to break open. So I was anxious to get back, and we returned to do a series of experiments then, using microbial genetics by the way to some degree, to figure out the entire pathway of fatty acid biosynthesis and how fats are regulated and all that stuff. That led to my work and ultimately into complex lipids and some work in cholesterol. So my career was helped enormously and broadened enormously by interacting with Jacques Monod.

Oh yeah, well I had made the decision at NIH to become more and more involved in biochemistry because I was pretty much pulled in by my own research and the excitement that was ongoing. So by the end of 10 years, my patient care had dropped enormously from half time to very little time, and I was concerned that I had given up my relationship to real medicine. I thought going back to a medical school at that point would be useful from the point of view of returning to medicine. Washington University was very attractive because the job I was moving into was that which had been held by Carl Cori, who obviously was a terrific biochemist and someone who really trained most of the senior biochemists in the United States. So it was very flattering, it was a great medical school, and one of my best post-docs was from St. Louis and who talked it up, Phil Majerus, whom you might know. He was going to go back there and he urged me to accept this job. We did, and it was a wonderful move to go to a place like both Washington University and St. Louis, because that was 1966 and things were just booming.

Well, as a researcher and as a teacher, I had a blossoming of my research. So much of the work that we did in lipids was carried out there, nine years worth. On the teaching, I was very anxious that people learned biochemistry, so I took a position that was largely focused on medical students and expanded it to more teaching of graduate students and then even undergrads. I really liked interacting with undergraduates, which surprised me initially. But the perhaps two most lasting things that I did at Washington University is that I started the MD-PhD program, which turned out to be one of the strongest ones in the U.S., not because I started it but because it was at Washington University and the kind of faculty that they have there.

Yeah, that was a dramatic change. There are a couple of things that were involved. One was that I knew Merck very well, not only from my interaction with the scientists in our restaurant, but also I was an intern at Merck one summer between my first and second year at Columbia Medical School. The person whose laboratory I worked in had kept up with me over the years by just meeting me at scientific meetings. That was of course 1951, so by the mid-70s I had seen him a number of times, and I was clearly a good biochemist, I was pretty well known at that time for my work. I was called and asked whether I would consider returning as head of research. I said no, I had no interest in going into industry. But at the same time, I was called by two major medical schools, Penn and the University of Chicago, and told that I was a top choice of their committee to become dean. That was very depressing for me because the idea of a deanship, I had observed the dean of Washington University, and that was not my cup of tea. The idea of not being in science at age 45 was abhorrent, and so I was deeply depressed by that idea. Then when approached by Merck and they asked to visit, I visited the research labs and what I found was exciting people who were interested in drug discovery, something I had never thought about. What they were doing for drug discovery was using live animals of various diseases, high blood pressure, infections, and inflammation, which they would set up a model of the human disease, and then the chemists would make chemicals which would be fed or injected into the animals. The chemists had no idea what the targets of what they were trying to treat were. I thought that was not optimal, and as a biochemist I said, 'Gee, as I thought about drugs and looked back at the literature, there's no question that one could be more effective in drug discovery if one selected individual molecular targets.'

Sure. Well, Al of course is a terrific person, and as I said, he worked with me in biochemistry in all these places that had been before. We published numerous papers together. In speaking with him, I didn't have to finish a line, he knew what we were talking about. We're very close personally as well. I suggested that one area that at that time was ripe was the area of cholesterol biosynthesis. Konrad Bloch at Harvard and Theodor Lynen had just figured out the total synthesis of cholesterol and its regulation, with it just being probed by Brown and Goldstein. So it was a project that was right for a biochemical approach. So Al and I agreed that that would be one of our first things that we would work on, and he would run the project. The target was the HMG-CoA reductase enzyme. It was known at that time, it was shown by a person in Lynen's laboratory, that that was the limiting reaction in cholesterol biosynthesis, the sequence of about 20 reactions where one reaction was rate limiting and therefore possibly could be blocked and block the whole sequence, reduce the amount of cholesterol that was formed in the body. Now that was the time the cholesterol hypothesis, that is, people had all kinds of evidence that high blood cholesterol could be related to heart attacks in coronary heart disease. It was a hypothesis. The knowledge of the pathway, the epidemiology which demonstrated such things as people in Japan had a very low incidence of death from heart attacks and extremely low average blood cholesterol levels, whereas people in Finland had an incidence of death from heart attack that was 14 times higher than those in Japan, and their blood cholesterol levels were sky high. This relationship between blood cholesterol and death from heart attack was a straight-line relationship across the globe. So all that information was available. Al and the group started working in this area, targeting HMG-CoA reductase, looking for an inhibitor. Just as we were starting up, of course we heard of Endo's work in Japan and the discovery of compactin, which was a natural product. Merck had lots of experience in natural product studies, so that was going to be the approach, a natural product and a chemical looking to find something that would block HMG-CoA reductase. Right at the beginning, we hear that we're already behind, but that wasn't so bad. I mean, that's research, you're always potentially behind a competitor, but you work to catch them. Al pushed on, and what we learned was that compactin did exactly what was predicted, blocked an enzyme reversibly, it was a competitive inhibitor of that enzyme, and in animals and then in humans it reduced blood cholesterol. Of course we didn't know at the time that it was having an indirect effect on the LDL receptors, we were just focused on what we were able to measure. Within a short time, Al came up with lovastatin, and lovastatin was able to do what compactin did, it was a reversible inhibitor of HMG-CoA reductase, it was safe in animals, and we raced into the clinic. We were very excited to see that not only compactin then, but lovastatin looked like it was able to reduce cholesterol levels in humans. It was very exciting, and it was a race. But then unfortunately, a rumor derailed you for a little while, a rumor that was devastating. Here we were very excited about what we were doing, and suddenly we heard from Japan that the clinical studies of compactin had stopped, and they had been stopped with no reason given, but a rumor that the compound caused tumors in animals. That was a tremendous worry. I got on the phone, called the people at the company where Endo was working, which was Sankyo company, and I told them that we had an inhibitor that was also from natural products that was aimed at the same enzyme, and it is possible I said that all inhibitors of this enzyme could do whatever you saw. I said, 'What can you tell us exactly what you're seeing?' And they said no, it's an industrial secret. So we could get no information, but the possibility that compactin was in fact causing tumors and that our inhibitor could do a similar thing caused us to stop all clinical studies that day, because we were not going to put any humans at any risk of potentially getting cancer.

Yes, yes, it was. It was the NIH and the FDA who were concerned that there was a potential drug to lower blood cholesterol. They were still believers of the hypothesis. There are people dying because they have high blood cholesterol, and here was a drug that could possibly change that. So they asked us to go back, but we lost two years on that basis. We went back to the clinic, but because of the concern, we went into high-risk patients, patients who had high blood cholesterol but already had coronary heart disease. All the studies with Mevacor, which was lovastatin, were done in such patients. At the end of the studies, it was found that the drug reduced blood cholesterol, specifically LDL cholesterol, and it was safe. So in 1987, the first statin in the world was introduced, and it was very exciting.

Well, that's a very interesting story. Of course I didn't mention it because ivermectin is not used in the general population, so the impact worldwide is much greater in other drugs and vaccines that I was involved in. But it was a wonderful story because it was a discovery at Merck again. Many of these compounds were. Bill Campbell was involved in demonstrating how important it was in parasites. It was more potent when it was discovered, it was a product from a natural product again. Ivermectin, he demonstrated that it could kill parasites with a potency about a hundred times greater than any known drug at the time. So we were anxious to get it into humans, but human parasites, tapeworm and hookworms, are not very susceptible. So it was put on the shelf while we developed this as a drug to kill parasites in animals, round worms largely, for started with horses and cattle, sheep, pigs, and ultimately also dog heartworm, very susceptible. So it was developed for all these uses. If you have a dog and treat your dog once a month to prevent heartworm, that is ivermectin. So it was a very interesting and important drug. It worked through a glutamate-driven chloride channel, so it was a very interesting mechanism of action. But in about 1981, Mohammed Aziz, who was one of our clinical doctors who had been in the World Health Organization in sub-Saharan Africa, came to tell me about river blindness and noted that there are 18 million people who were infected and going blind on the basis of a parasite called Onchocerca volvulus, and that there was not a good drug for the treatment of this disease. Perhaps ivermectin could do that. So he asked whether he could take some. We packaged it into a tablet form, called it Mectizan so it would look different and be referred to differently, and he went off to West Africa, Dakar in Senegal, where he undertook to treat some of these patients who had this parasitic disease. The disease is caused by a worm, Onchocerca volvulus, which exists as an adult worm and a microfilaria, the babies. These microfilaria live in the skin. The way it works is that a black fly, which is the vector, bites someone who has the microfilaria in the skin, picks up microfilaria, and within the fly the microfilaria develops so that when that fly bites another person, it injects a form that can become an adult. The adults, the males get to be about four to six inches, the female is about 16 to 18 inches, they live together in lumps about the size of a small half of a ping-pong ball in the skin. So you can see these people with these lumps. Within this lump, these males and females make microfilaria which crawl all through the skin and cause enormous itching. This itching drives them crazy, they're scratching constantly. But the worms, these microfilaria, also migrate into the eyes, and there they cause inflammation and ultimate hardness of the eye, and they become blind. So Mohammed went there and took little skin snips over the hip of some of these patients who obviously had river blindness, and counted the number of worms, microfilaria, average would be 15 in the little snip of skin. Then he gave one tablet of ivermectin to each patient, then came back in a month, and he took a snip of skin again, and there were none. So after one tablet, they were all gone. So he came back, he was very excited, and I was excited when I saw the results. We talked with the World Health Organization specialists, who said the results were probably wrong because there's no way that a drug could eliminate all the microfilaria without causing serious side effects, the protein for getting into the body at that level would cause side effects. So they didn't believe the results and they walked out. Well, we of course knew the results were correct, and we carried out a large development program, knowing that the people who would take the drug were among the poorest in the world.

Yeah, that was a problem. Our marketing people thought we would certainly come up with some way to find a price that was appropriate, including selling it to governments, but the governments had different priorities. Neither in Africa nor the U.S. government, where I visited both with the Deputy Secretary of State John Whitehead and the president's chief assistant, who at that time was Donald Regan, Reagan's chief of staff, both of them saw these were fabulous results and would be very exciting. John Whitehead said, 'We're going to have the American flag all over Africa.' I said, 'Yeah, yeah, yeah.' But then I'd walk out and the assistant would tell me, 'Look, this is very exciting, but we have no money in the budget.' I said, 'We're talking about two million dollars to start a program,' and they said, 'But we just don't have it in the budget.' So we were left. Our executive group, by then I was CEO of the company, of course, and I was meeting with the executive group trying to figure out how we're going to get this drug to the patients. We had filed the results with the French regulatory authorities because the FDA didn't know about river blindness, there is no river blindness in the U.S., but in Paris there are French people living with river blindness because of French Africa. So we had filed it with the French authority, expecting that it would take very long to be reviewed because that was the usual rate of work at the agency, when we were suddenly called and told, 'Next Monday we're going to approve the drug.' At that point, we did not know how we were going to get the drug out. So we met quickly, the executive group, and we said, 'You know, we've got this almost magical...' Oh, I didn't tell you, it was picked up by the New York Times, and there was a cover story on Sunday, the cover of the magazine section had river blindness on the cover, two older people who were completely blind being led by a young person on a stick, which was typically what was going on in these villages. Some villages have 25, 30 percent of the adults were blind. So they had a story on river blindness and that Merck had a drug that was almost miraculous, magical drug. What was Merck going to do with it? So the pressure was really on. We met on the Monday morning, we had a press conference in Washington and announced that the company would make that drug available to anyone in the world for as long as it was required.

That's really inconceivable. I grew up in that world. From early days, I saw my parents how hard they worked in order to get that I received a good education and do something beyond that. So that never crossed my mind really. I was going to do something else. Could it have been? It could not have been anything other than science, because I always went in that direction. Everything I did when I was CEO, I was still essentially running the research labs with a head of research, but I was very close to him because that's what I know. The business aspects, I make a point of this in talking with my students that I'm engaged with. By the way, it's a large group of students because the idea is to take 25 freshmen each of these three programs every year, so four years worth, it's a lot of students that I see. They're all Vagelos Scholars of Penn, which is very exciting for me. So directions are always what is interesting at that time. Fortunately, I'm still interested in things that are based in science, and that's what's so exciting. You can make dramatic changes in the way people live, and you can help people through science. That's what I've learned, and I don't know what I would have done had it not been in medical science. I can't believe it could be anything else. I can't understand why anybody would work in any other field.