Scott Montgomery Grundy, MD: a conversation with the editor∗

SCOTT MONTGOMERY GRUNDY, MD: A Conversation With the Editor* ince 1981, Scott Grundy has been Director of the Center for Human Nutrition at the University of S Texas Southwestern Medical Center in Dallas. He grew up in Memphis, Texas, went to Texas Technological College in Lubbock on a basketball scholarship, graduating in 1955 with honors, and then he went to Baylor College of Medicine in Houston, graduating in 1960 with both a Masters of Science and an MD degree. His research in lipids began as a medical student. After brief training in internal medicine and in pathology in Houston, he went to Rockefeller University in New York City, where he obtained a PhD degree in 1968. From there, he went to Phoenix, Arizona, as Chief of the Clinical Research Section of the National Insitute of Arthritis and Metabolism. From there, he went to the University of CaliforniaSan Diego in 1973, where he remained for 8 years. Virtually his entire investigative career has been directed toward understanding atherosclerosis and preventing and arresting it. He was among the first to demonstrate the effectiveness of the statin drugs. His contributions to our knowledge of lipid metabolism have been enormous, and they have led to the publication of nearly 500 articles. Dr. Grundy has played a leading role in formulating the guidelines for using lipid-lowering therapy. He is also a splendid man with a good sense of humor and graciousness that makes him well liked by all fortunate enough to know him. WILLIAM CLIFFORD ROBERTS, MD† (hereafter WCR):

I am talking with Dr. Scott Grundy in his conference room at the University of Texas Southwestern Medical Center on July 15, 1998. Dr. Grundy, I appreciate your willingness to talk with me so that the readers of the American Journal of Cardiology will get to know you better. I have been following your work for a long time. You are one of my heroes, so to speak, so I am really pleased to be here. I understand that you were born in Memphis, Texas, on July 10, l933. Is that where you grew up? Tell me about Memphis, Texas.

SCOTT MONTGOMERY GRUNDY, MD, PhD‡ (hereafter SMG): Bill, Memphis is a small town in the Pan-

handle of Texas. It is 90 miles southeast of Amarillo. When I grew up there, it was a town of about 5,000 people. It has since shrunk to about 3,500. It is a farming and ranching community. Mostly cotton and cattle feed are grown on surrounding farms, and cattle are raised on small ranches. It was a fine place for me to grow up. I lived there until I went away to college. My father, Allen Grundy, farmed and practiced law. We owned a farm 11 miles from town. Unfortunately, *This series of interviews underwritten by an unrestricted grant from Bristol-Myers Squibb. † Executive Director, Baylor Cardiovascular Institute, Baylor University Medical Center, Dallas, Texas 75246. ‡ Director, Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, Texas 75235. ©1999 by Excerpta Medica, Inc. All rights reserved.

my father died when I was 10 years old. He was a good father for the time I knew him. My mother, Beulah Montgomery Grundy, also called Boodie, was a marvelous mother to me. She was well educated, studied constantly, and was interested in education. She even went back to college in her late 50s to complete her college degree. She was supportive of her childrens’ education and undoubtedly played the major role in my early development, which set the stage for my later career. WCR: What do you remember about your daddy? SMG: Mainly, I remember going to the farm with him from time to time. He seemed to work hard, and I remember him dressed in work clothes. Although he practiced law, I was not much aware of this aspect of his life. WCR: Did he die young of heart disease? SMG: I believe not. There was no talk about a heart attack. He was admitted to our little hospital in Memphis. Something went wrong with him, and suddenly he died. Our family was never quite clear what went wrong. We never had a definite diagnosis to my knowledge. WCR: Was this his first illness? SMG: As far as I know, it was. He was 47 years old when he died. I believe he had been in fairly good health. In those days it probably was dangerous to go into a hospital. Maybe the same is true today. WCR: How many siblings did you have? SMG: I had 1 brother, Larry, 7 years older and a sister, Elizabeth, 2 years younger than I was. WCR: Your mother was really the one who brought you up? SMG: Definitely. She was the central person in my early life. WCR: Did she work? SMG: Not outside the home. She raised the kids. In those days, mothers usually didn’t hold an outside job. We had aunts, uncles, and grandparents nearby. There was a strong family structure that was supportive, but demanding on my mother. She took on the task of keeping our extended family together and going. She also was an important member of the community, especially in her church. She remained in Memphis for her whole life. Most of her siblings left the town. She assumed the responsibility for caring for my grandparents in their later years. WCR: So your mother’s and your father’s parents grew up in the vicinity of Memphis, Texas, or close by? SMG: My grandfather on my mother’s side, Steven Scott (S.S.) Montgomery (I am named for him), and his father, James Clowney Montgomery, came to the Texas Panhandle in 1889, and they actually organized the town of Memphis, which became the country seat of Hall County. My grandfather was born on a ranch 0002-9149/99/$–see front matter PII S0002-9149(98)00849-2

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FIGURE 1. SMG at the time of the interview.

10 miles east of Sherman, Texas, in Grayson County. His early home was near a small town called Whitewright, Texas. He told his grandchildren many wooly tales of his childhood there. His parents had come to Texas from Alabama, trying to escape unhappy lives after the Civil War. S.S. served as sheriff of Hall County from 1894 to 1898. He eventually became the President of the First National Bank of Memphis. He was a co-organizer, director, and elder of the First Presbyterian Church which came into being in 1900 (most of the other 13 original members were relatives). He was a pillar of the community until his death at age 94 in the 1960s. In 1891, S.S. married Lulu May Walters, who was a music teacher living in Vernon, Texas. S.S. and Lulu had 5 children, of whom my mother was the youngest. My grandfather was a most important person in my life from very early. After my father died, he served as the male figure in my life. Working with my mother, he took good care of me, and also inspired me to intellectual pursuits. His involvement with the Presbyterian Church, along with that of most of my relatives in Memphis, ensured my participation in church activities. On my father’s side, my grandfather was Joe Grundy. I didn’t really know him; he died when I was a baby. Joe Grundy and his brother came to the Panhandle in 1889 from Kentucky; they settled in a small community called Newlin, which was about 10 miles south of Memphis. The Grundy brothers sold real estate and farmed. In the early 1890s Joe returned to Kentucky to fetch Lucinda (Cindy) Clack to be his 224 THE AMERICAN JOURNAL OF CARDIOLOGYT

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wife. They moved to Memphis some years later after my father was born. They too became regular members of the Presbyterian Church. Cindy, my grandmother, lived until the 1950s and died of “old age” in her 80s. In many ways she was my real “grandmother.” She had a wonderful house, and usually our family had lunch (then called dinner) at her house every Sunday after church. WCR: Your mother and father knew each other growing up? SMG: My mother was born and raised in Memphis. My father moved there with his parents from Newlin. I don’t know the circumstances of the meeting of my mother and father, but undoubtedly it was in the Presbyterian Church, which was at the center of social lives in those days. My father was 7 years older than my mother; he was born in 1896, and my mother in 1903. He went to the University of Texas in Austin, and during the First World War he was commissioned after schooling at Virginia Military Institute (VMI). He did not go to France, however, during the war. WCR: Your mother was the intellectual one. She stressed education. SMG: Yes. She had considerable schooling for a small town. She was in the very first class of the Hockaday school for women in Dallas, and in the early 1920s she attended Trinity College, which then was in Waxahachie, Texas. Trinity University was affiliated with the Presbyterian Church; it has since moved to San Antonio, Texas. However, the old school buildings that were Trinity are still in Waxahachie, but are used for some other purpose. My mother was never happy that she had not received her college degree, and in her late 50s, she went back to college, took courses, and obtained her degree. WCR: What did your older brother do? SMG: After he finished high school in Memphis, Larry went to college for about a year at the University of Texas in Arlington; then in l943, he went into the Navy. At the end of World War II, he went to Baylor University in Waco, where he majored in chemistry. There he met Mary Alice Thompson, who was from Palestine, Texas, and they were married. After graduation and marriage, Larry and Mary Alice went to Oklahoma A&M, Stillwater, Oklahoma, where he received a masters degree in chemistry. Then he became a teacher at Clarendon Junior College in Clarendon, Texas. He taught there for several years before going to work with Phillips Petroleum Company, first in Borger, Texas and then in several other places, including Bartlesville, Oklahoma (the company’s headquarters). While working at Phillips, Larry was offered a job on the East Coast; he and his family (wife and two children) moved to Boston, where he became the director of a factory making plastic items. After several years there, he was transferred to Maine. Later, he took a similar job with a larger company in New Jersey. Unfortunately, he became afflicted by chronic lymphocytic leukemia, and sadly, suffered for a long time before he died a couple of years ago. WCR: What has your sister Elizabeth done? JANUARY 15, 1999

SMG: After graduating from high school, Elizabeth went to college at West Texas State College in Canyon, Texas. Canyon is right outside of Amarillo. There she met and married Gene Murray. They have since lived in Canyon and have two sons. Both Elizabeth and Gene have taught in public schools. Elizabeth taught in Amarillo, Texas, and still does. Mainly, she has worked in special education with disadvantaged children. She spends almost full time thinking and planning how to improve educational techniques. She is a devoted teacher and has tremendous energy that is directed almost entirely to her teaching work. She has made many contributions to the public educational program in Amarillo. Her husband, Gene, taught in the Canyon school system for many years. However, he retired a little early so that he could pursue his creative and artistic interests. Gene is enormously talented, being both musically and artistically inclined. Although he has always been creative, his productivity mushroomed after his retirement. He plays a key role in planning, set and costume design, and singing in the Amarillo opera. Even more impressive is that the fact that he writes his own operas. Several of his operas, which are mostly of Western genre, have been produced in the Amarillo area. You will recall the story of the supposed landing of the unidentified flying object (UFO) in Roswell, New Mexico, in the 1950. Roswell has become the Mecca of the UFO crowd. Gene recently wrote an opera about this event, and it premiered in Roswell this summer. I am told it will become an annual event there. I have seen several of Gene’s operas. They grasp the essence of the West and transform it into music. WCR: What was it like growing up in Memphis, Texas? Did you live in town? SMG: Yes, my family owned a farm and I used to go there with my father. I didn’t like farm work, however. To me the work was boring, and early on, I knew I was destined not to become a farmer. You always had to worry about the weather and crops, and the worries were the same, year in and year out. There was nothing in farming that interested me. Instead, I stayed in town and did things there. I was mainly interested in sports. I liked school, and the combination of school, sports, and church largely made up my childhood and adolescence. WCR: You grew up in Memphis in the 1930s during the Depression? SMG: I was a small child in the 30s, but went to school in the 40s. WCR: Do you remember the Depression at all? Was it talked about? SMG: I remember it being talked about, but I don’t recall any financial hardships. Instead, I remember the dust storms that occurred at that time. They are indelible in my mind. To me they are somehow linked to the Depression. There were days when one literally couldn’t see across the street because the sand was so thick. This was not unusual. But I don’t remember any money problems. We were never hungry or suffered in any way.

FIGURE 2. SMG at the time of the interview.

WCR: You say you liked sports better than farming. What sports did you play? SMG: Baseball and basketball. I liked them both. One year while I was playing, our high school basketball team won the state championship. It was thrilling. Furthermore, I went to Texas Tech University on a basketball scholarship. I had more talent for basketball, but actually liked baseball better. WCR: What positions did you play in baseball in high school? SMG: Outfield and first base. I was in love with baseball. The essence of my feeling about baseball is caught in Ken Burn’s recent video documentary of the American baseball experience. WCR: Did you like your studies in high school? Did you work hard? SMG: I did work hard, but school was easy. Sadly, high school work was not very demanding. Nevertheless, we had 2 or 3 exceptionally talented teachers who were inspirational and stimulating. They deserve credit for starting me off on the right track in academics. WCR: Which high school teachers had the greatest influence on you? SMG: There were 2 who inspired me academically. One was Elsie Guthrie, who was a brilliant English teacher. She would have made an outstanding college teacher. The other was Neville Wren. Miss Wren had been the Director of the Department of Chemistry at Lubbock High School, before moving back to Memphis to care for her elderly mother. Her taking a job in INTERVIEW/SCOTT MONTGOMERY GRUNDY

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FIGURE 3. SMG as a senior in high school.

FIGURE 4. SMG (far right) as a senior in high school on the championship basketball team.

Memphis High School was a stroke of luck for me. She gave me a solid foundation in chemistry (which I didn’t have in other subjects), and this made college chemistry much easier for me. WCR: How many students were in your senior class in high school? SMG: About 38. WCR: So you graduated number 1 in your class of 38? SMG: I was either first or second. WCR: So you enjoyed your school work and worked hard? SMG: Yes, but it didn’t challenge me. I realized how limited my education was when I got to Texas Tech and had to confront students from “big” cities like Lubbock and Dallas. It was obvious that they knew a lot more than I did, and it took me awhile to catch up. WCR: You mentioned your church activities in Memphis. What was it like? You went to Sunday school and church regularly? Maybe church dinners on Wednesday night? SMG: Right. Much of the social life in our town revolved around the churches, for our family, the Presbyterian Church. Our church had good ministers, and we also had regional programs for youngsters. Every summer I went off to church camp where we came into contact with some remarkable people, among whom were Presbyterian missionaries who worked in foreign countries. They would talk to with 226 THE AMERICAN JOURNAL OF CARDIOLOGYT

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us about the wonderful things they were doing and how they were saving lives as well as souls. Some told about their work in Africa, Asia, or parts of South America. Their stories broadened my outlook beyond the bounds of Texas. WCR: What were the effects of your early religious experiences on your later life? SMG: They were considerable, and in several areas. Presbyterians seem to intellectualize religion. Presbyterianism is a form of Calvinism, and it stresses a stern, intellectual commitment to God and mankind. Our religious studies were strong on church history, and they broadened my interests into history in general. To me, Calvinist theology has a strong philosophical bent, and readings in theology sparked what became a prolonged interest in the history of Western philosophy. These interests were heightened by contact with learned ministers from the regional Presbytery, and they have remained with me throughout life. In addition, my religious experiences and associations opened my eyes to the plight of mankind. Stories of missionaries vividly revealed to me the extent of human suffering throughout the world. These impressions undoubtedly had an impact on my thinking that influenced my later career decisions. I was less affected by religious dogma. In religion I was more inspired by Albert Schweitzer than by Billy Graham. The uncertainties of religious doctrine left me with little desire to try to save souls. Insight into human JANUARY 15, 1999

FIGURE 5. SMG at graduate ceremonies at high school.

suffering had yet another influence with regards to my career. It created a barrier to pursuit of pure science that is not tangibly linked with human end points. But all of this religious influence acted at a deeper level and came out later. My true preoccupation in high school was with sports, which didn’t seem incompatible with the religious life. In fact, church on Sunday morning didn’t keep me away from baseball games on Sunday afternoon. But I can assure you that in close basketball games we prayed earnestly for God to side with our team. WCR: So when you finished high school, you chose to go to Texas Tech. How far is Lubbock from Memphis? SMG: One hundred fifty miles. WCR: How did you choose to go to Texas Tech? I assume all your tuition was paid since you were on a basketball scholarship. SMG: Correct. I had to choose between TCU (Texas Christian University; Fort Worth) and Tech (Texas Tech). Although I went on an athletic scholarship, I made the decision on academics. For some reason, I thought Texas Tech was better academically. WCR: When you got to college, what happened? SMG: I started out spending much of my time on basketball practice, as required by the athletic scholarship. Fortunately, in retrospect, I was not a collegecaliber player. After about one and a half years I came to realize that basketball held no future for me, so I began to get more serious about my studies. WCR: Can you tell me whether there were any long-term beneficial effects of your youthful experience with sports?

SMG: One of my life-long characteristics has been an intense preoccupation with the subject of current interest to me. When I was involved in sports, it was serious business. As such, I found both baseball and basketball to be demanding and molding activities. They required mental and physical exertion and endurance. They also forced me to come to grips with my limitations. In addition, team sports reveal that success can only come through teamwork. Of great importance to me, competitive sports teach us to never give up; one can never tell when fortune may smile at the last moment, as it sometimes did for me. At least for me, intensive involvement with sports was a preparation for coping with adult life. I have come to see the wisdom of the inscription at the entrance to the athletic fields at West Point, that is, what is learned here will bear the fruits of victory “upon other fields, on other days.” Without the experience gained from those long hours of exertion and competition in high school and college, I truly doubt that I would have been able to sustain the ups and downs of a lifelong career in research. Like the batter at the plate, in medical research there are many more outs than hits, and homeruns are few and far between. WCR: So you turned to academic work. What was your major? SMG: Chemistry. WCR: Your brother also majored in chemistry? Who had a scientific impact on your back in Memphis? SMG: My brother had an influence, as did my high school chemistry teacher, Neville Wren. WCR: Did Texas Tech provide well for you academically? SMG: Again, fortunately, Texas Tech was an excellent place for an education. They had wonderful teachers who took great interest in the students. My mind was opened up to a new world of learning, which went far beyond anything I was ever exposed to in high school. WCR: Did anybody at Texas Tech University have a major impact on you? SMG: There were 3 people in the Department of Chemistry who had the greatest influence. Margaret Stuart taught qualitative analysis. She was stern, but caring and committed. She took me on as a laboratory assistant. I remained her friend for the rest of her life. Joe Dennis was Chairman of the Department of Chemistry. He was extremely intellectual, an excellent teacher, and a good Presbyterian. He provided me with the fundamentals of biochemistry; fortuitously, I wrote a research paper for him: the biosynthesis of cholesterol. Robert Goodwin was the dean of Arts and Sciences, and later became president of Texas Tech. He taught me how to think about the reactions of organic molecules, but he did more than that— he gave me a solid grasp of the carbon backbone of the biological world. These 3 people were true role models. Other teachers at Texas Tech were excellent, particularly the science professors. After Texas Tech, I never had any problems with the academics of medINTERVIEW/SCOTT MONTGOMERY GRUNDY

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ical school. In fact, in medical school, I was scientifically way ahead of most of the other students. WCR: You went to college from 1951 to 1955, 4 years? How many students were at Texas Tech at that time? SMG: Five thousand. WCR: Did you live in the dormitories? SMG: I started out in the athletic dorm. That was an experience. I can assure you that the primary interest of most of my teammates was not academics. My view of college and professional athletes has been rather jaded ever since. However, the dorm kitchen fed us better than all the other students on campus— one plus. WCR: How tall are you? SMG: Six feet, 3 inches. WCR: How much did you weigh then? SMG: I weighed about 190 pounds, more than I do now. But it was all muscle then. WCR: After you gave up basketball, did they take your scholarship away? SMG: Of course. I had to come up with the tuition afterwards, but it was cheap enough. WCR: What is your assessment of your education at Texas Tech? SMG: In those days Texas Tech was quite strong in science and engineering. I tried to take full advantage of this strength. Not only did I receive a strong grounding in organic chemistry and biochemistry, I fell in love with these subjects. Thereafter, I always thought in molecular terms. I have since visualized biological processes as molecular events. I have no doubt that my experience at Texas Tech laid the foundation for my academic career. Upon entering medical school, I gravitated toward research and biochemistry. This love and understanding of molecular processes provided a balance to humanistic tendencies acquired through religious experience and made it unlikely that I would pursue a career in the routine practice of medicine. WCR: Where did you apply to medical school? SMG: At first I applied to two Texas schools: University of Texas Medical Branch at Galveston and Southwestern Medical School in Dallas. I was accepted at Galveston without an interview. I interviewed in Dallas at Southwestern, which was then housed in old U.S. Army barracks on Oak Lawn Ave. Parkland Hospital also used to be on Oak Lawn. When Baylor University College of Medicine moved to Houston from Dallas in 1943, there was no medical school in Dallas for awhile. Then an influential group of citizens organized Southwestern Medical School, which was later affiliated with the University of Texas. When I visited Southwestern and its barracks, I said to myself “This is a medical school?” But I was resigned to go there nonetheless. WCR: But you ended up at Baylor Medical School in Houston. SMG: At first I did not even apply to Baylor because tuition was $1,000 per year, and that was out of my reach. Then fate intervened. At Texas Tech, we had a pre-med club and one of our invited speakers 228 THE AMERICAN JOURNAL OF CARDIOLOGYT

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was James Schofield, Assistant Dean at Baylor. I sat next to him. Dr. Schofield was an aggressive recruiter of good students for Baylor. We chatted, and he asked why I had not considered Baylor. I said I couldn’t afford to come to Baylor. He told me that perhaps Baylor could give me a scholarship ($500 per year), and he offered to pay my way to come to Houston for an interview. I got on the train and went to Houston. Baylor Medical College had a brand new building, quite a contrast to Southwestern’s barracks. Several things attracted me to Baylor besides the scholarship and facilities. The fact that someone actually took a personal interest in me was appealing. Also, Baylor only had 3 examinations per year! The rest of the year you could study and prepare, but did not have to sweat out the every Saturday morning exams that I had been warned about at Southwestern and Galveston. Dr. Schofield also told me that Baylor fully intended to graduate all of its students, and would not flunk out a sizable portion of the class. I had heard tales of large numbers of students flunking out of the other schools in Texas. Being from a little town in the Panhandle, I was not filled with confidence in my abilities. So I chose Baylor to be on the safe side. I often reflect on this chance encounter with James Schofield and wonder how my life would have been different if I had not met him and had gone to Southwestern instead. Perhaps not so badly. I would have been a student of Dr. Donald Seldin! Not having been one of Dr. Seldin’s boys has been one of the regrets of my life. Just look at the great researchers and teachers who grew up under him, Drs. Jean Wilson and Daniel Foster, for example, not to mention Joseph Goldstein. WCR: You had to come up with another $500 to go to Baylor. SMG: That wasn’t too hard, particularly after I got married and my wife worked. WCR: Why did you take 5 years to graduate from medical school? SMG: I took an extra year and participated in their masters degree program. At Baylor, students could get a masters degree while going to medical school. They split their second year, and thus had half-time in research for two years to work on it. Many students who entered this program ended up in academic medicine. Some of them became quite well known. Providing research training for medical students was visionary on Baylor’s part. I’m sorry we don’t still use Baylor’s model in our medical schools. We don’t do enough to encourage our bright medical students to pursue research and academic careers. WCR: When you entered Baylor University College of Medicine in Houston in 1955, how many students were in your class? SMG: Ninety. WCR: How did you find medical school? Did you enjoy it? SMG. It was a tremendous experience. I enjoyed every minute of it. The teachers were terrific. Everything Dr. Schofield said was true. The faculty really supported the students. There was no undue pressure. JANUARY 15, 1999

We studied hard, but I loved it. To me, Baylor was a fabulous place to receive a medical education. WCR: Who had an impact on you? SMG: It is not fair to single out individuals, because so many contributed. But 2 do stand out. One was Clark Griffith, Chairman of the Departments of Biochemistry at both Baylor and M.D. Anderson Hospital. He was a cancer biochemist of considerable renown. Strangely enough, despite his cancer interests, Dr. Griffith is the person who got me started in atherosclerosis research. When I entered the masters degree program, I decided to work with Dr. Griffith. He said to me one day that the Anderson-Clayton company wanted Baylor to do research on the potential of one of their products, lecithin, to prevent atherosclerosis. The company offered to buy the Biochemistry Department an analytical ultracentrifuge, which at that time cost $30,000, if Dr. Griffin would study the effects of lecithin on lipoproteins. This centrifuge was championed by John Gofman and his team at Berkeley. Gofman had recently “rediscovered” the serum lipoproteins and had developed a method for analyzing them with the ultracentrifuge. John Gofman was truly a genius, and deserves enormous credit—much more than he has received—for his contributions to the fields of lipoproteins and atherosclerosis. He clearly delineated very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and highdensity lipoprotein (HDL) as separate lipoproteins. His methods of classifying lipoproteins are still used today. He also was prescient in predictions of the atherogenicities of the different lipoprotein species. Dr. Griffin asked me if I would like to work on this project for my masters degree. I agreed, was given complete control over the ultracentrifuge, and was allowed to follow my own interests. Incidentally, I found that feeding lecithin to rabbits doesn’t improve their lipoproteins or prevent atherosclerosis. Of interest, I was taught to use the ultracentrifuge by researchers at the Air Base in San Antonio, who were measuring lipoproteins prospectively on West Point cadets and pilots. They ran thousands of samples, but unfortunately, none of their studies ever made it to the scientific literature. WCR: What did you learn in your lipoprotein research? SMG: I did naive studies on effects of solvent extractions in the attempts to get at the protein core of lipoproteins. In fact, this work resulted in several publications, although the tools were not available to do definitive work on the apolipoproteins. Of more substance was the observation that mental stress raises serum cholesterol and lipoprotein levels. There was a hint of this in the literature before, but I believe that I really nailed it down. Since the medical students had their exams every 3 months, the pressure would mount so that on the day of the exam, when they were in a state of panic, their cholesterol levels were much higher than in the relaxed period between exams. I reproduced this fluctuation several times over 2 years. WCR: So by the time you graduated from medical school you had written 10 papers?

SMG: Yes. WCR: When you interview people now to work in

your laboratory, do you always look to see if they published when in medical school? SMG: That is a plus, but unfortunately, we rarely see much evidence of student research because medical schools don’t give their students a chance to be involved in research as Baylor did. I have tried to rekindle interest in the Baylor model, but with little success. In my view, a great opportunity is being missed. WCR: Who was the other influential person at Baylor? SMG: Michael E. DeBakey. Dr. DeBakey was previously interviewed by you for this series. He truly is one of my heroes. When I was in medical school, he was just an incredible man, almost superhuman, a person way beyond the ordinary in talents, skill, and knowledge. He was an inspiration to me, and still is. He was also working on atherosclerosis. Although he suggested to me that I should consider surgery as a career, and has continuously admonished me afterwards for my mistake, surgery was not to my taste. Nonetheless, he was supportive and helped me get funding for my research on atherosclerosis and lipoproteins. Dr. DeBakey taught me how to apply oneself to work and how to make things happen. He was incredibly good at making things happen; he, more than anyone, built Baylor into what it is today. WCR: When did you decide you liked research and that research is what you wanted to do? SMG: As I mentioned, the stage was set by my college studies, but my association with Dr. Griffith was the precipitating influence. In fact, when I finished medical school, Dr. Griffith wanted me to go straight into the Department of Biochemistry, which I did. However, I received another opportunity that gave me a boost in this direction. I was invited to work in the laboratory of Prof. Sune Bergstrom of the Karolinska Institute in Stockholm. This was made possible because of Sune Bergstrom’s visits to the newly formed Lipid Research Center in Houston headed by Evan and Marjorie Horning. Dr. DeBakey was a strong supporter of this new center, and he obtained funding for me to spend a summer in Bergstrom’s laboratory. Sune Bergstrom was a co-discoverer of prostaglandins, for which he received the Nobel Prize. Also, his laboratory was working on bile acids, which was the subject of my research with him and his group. This experience opened my eyes to how good research is actually carried out. WCR: That was immediately after you finished medical school? SMG: Yes, 1960. WCR: Who were you classmates in medical school. SMG: My best friend was Malcolm Daniel, now a cardiac surgeon in Chattanoga, Tennessee. Another close friend was George Noon, now a well-known cardiac surgeon who worked closely with Dr. DeBakey throughout his career. Another was Wayne Bardin who has had an illustrious research career in INTERVIEW/SCOTT MONTGOMERY GRUNDY

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FIGURE 6. SMG with E. H. Ahrens, Jr. (left).

endocrinology at the National Institutes of Health and the Population Council of the Rockefeller Foundation. WCR: After you decided you did not want to be a surgeon, what did you decide you wanted to do? SMG: That is a good question. I could not decide immediately. I wanted to continue with research, but realized that I needed clinical training. So I gave up the Biochemistry position and started an internship in Internal Medicine. In a rotation on pathology, I met the new chairperson of pathology, Dr. Robert O’Neill, who was working on atherosclerosis. He convinced me to switch to a pathology residency and promised that I could work with him. WCR: Then the pathologist enticed you to come to the pathology department. How long were you there? SMG: A year. WCR: You did that so not much because you were interested in pathology, but in atherosclerosis and the new pathology figure was prominent in experimental atherosclerosis? SMG: That is exactly right. However, Dr. Griffith was not happy with this pathway and urged me to consider going to Rockefeller University to obtain a PhD. He used his influence to obtain an interview for me at Rockefeller. WCR: So you went to Rockefeller University in 1962? SMG: Yes, July 1962. Dr. Griffin made his last major contribution to my career by promoting this move. WCR: You stayed at Rockefeller University until what year? SMG: 1971. WCR: How did that work out? SMG: Rockefeller was even better than Baylor. The Rockefeller University at that time was absolutely at its peak. There were many famous scientists there. Detlev Bronk, the former President of the National Academy of Sciences, was its president. In the 1950s, at the request of David Rockefeller, Dr. Bronk had assumed direction of Rockefeller and had established 230 THE AMERICAN JOURNAL OF CARDIOLOGYT

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a graduate school. He also brought in many fine scientists. He changed the old Rockefeller Institute into a graduate university. When I reached Rockefeller, I was able to survey different laboratories and choose the one I wanted to work in. I was attracted to E.H. (Peter) Ahrens, Jr., who was doing outstanding work in lipid metabolism. He was a link to my interest in atherosclerosis. I continued to work with Pete Ahrens for almost 9 years, completing my PhD along the way. WCR: So you were doing basic research? SMG: No, not basic research. Pete Ahrens believed in clinical research; for him human research was basic research. He was committed to doing research in humans. In fact, he has been a strong advocate of clinical investigation for many years, and he certainly was influential in setting my research direction. I have focused on clinical research ever since. He deserves the credit for my being a committed clinical investigator. WCR: What you are doing now, in actuality, is similar to what you were doing at Rockefeller University in the 1960s? SMG: More sophisticated, but along the same lines. WCR: You also got some training in internal medicine and endocrinology while you were there. You were chief resident in the hospital? SMG: It was all research. After I finished my PhD, I went on the faculty. The Chief Resident at the Rockefeller Hospital was the person who coordinated all the clinical activities. It was not a training position. WCR: How many beds were in the Rockefeller University Hospital? SMG: Forty, when I was there. WCR: For both children and adults? SMG: Yes. WCR: Surgery? SMG: No, they were all research beds. Some beds were funded by NIH, and some by the Rockefeller University. WCR: Where is the Rockefeller University located? SMG: At 66th Street and York Avenue. It consists of a campus with several research buildings, including 1 hospital building. WCR: Where did you live in New York? SMG: East 77th Street and York Avenue. WCR: So you were close? SMG: Yes, I always walked to work. We didn’t even own a car. WCR: Tell me about your training at Rockefeller. SMG: Rockefeller was the defining experience of my career. Working with Pete Ahrens taught me to carry out human research and lipid research. In addition, I was exposed to many of the renown biological scientists of our time. We had day-to-day contact with these great people. Rockefeller was an open society. We had a common dining room where everyone came JANUARY 15, 1999

for lunch. One could sit down with Nobel laureates and members of the National Academy of Sciences and chat with them any day. Some of the faculty I knew personally included Fritz Lipmann, Edward Tatum, Henry Kunkel, Gerald Edelman, Lyman Craig, Stanford Moore, William Stein, Maclyn McCarty, Alexander Bearn, Rene Dubos, George Palade, Christian DeDuve, Richard Shope, Rebecca Lancefield, Vincent Dole, Bruce Merrifield, and Payton Rous. When Payton Rous was a medical student, he contracted TB and took the cure on a ranch in the Panhandle of Texas; he used to reminisce with me about those times. Dr. Bronk insisted that the PhD students get special attention, and we had ready access to all of these people. Many of the PhD students were close friends. My best student friend at Rockefeller was Anthony Cerami, who has made marvelous contributions to many fields, including diabetes, immunology, and aging. I have maintained a close relationship with him ever since. WCR: You did not have to pay to be there. They paid you? SMG: Yes, they paid me. This made it possible for me to go there. WCR: Can you describe the work you did there in those 9 years? SMG: Let me say that my research was carried out in a very active laboratory. Some of the researchers in Dr. Ahrens’ group were Norton Spritz, Jules Hirsch, Alan Hofmann, Gerald Salen, Tatu Miettinen, Robert Lees, and Jean Davignon. All of these researchers have become well known. My own research was focused on the development of the cholesterol balance method. This methodology aimed to define human cholesterol metabolism in quantitative terms. It measures how much cholesterol the body makes, how much is absorbed, and how it distributes throughout the body. It also measures the synthesis of bile acids, a product of cholesterol. Once the methods were worked out, we were able to study the effects of various nutrients and drugs on cholesterol metabolism. Pete Ahrens was one of the discoverers of the action of polyunsaturated fats to lower the blood cholesterol, and he wanted to know how polyunsaturated fats alter the body’s cholesterol metabolism. However, at Rockefeller, the development of new methodology seemed to be an end-in-itself. In the rarefied atmosphere of this institution, new methods appeared to be even more important than new biological discoveries. My own research attempted to expand on methods to study cholesterol metabolism, including use of radioactive tracers to follow the pathways of cholesterol into and out of the body. WCR: What was a typical day like in 1965 when you were working in the lab at Rockefeller University? SMG: The research was so exciting I spent almost full time at work. Of course, New York offered many cultural opportunities, and we took some advantage of these, when time and money permitted. On a day-today basis, most people came to work at 9:00 A.M., and I often stayed until 7:00 or 8:00 P.M. Still, there was a leisure quality to the research. There was not a great deal of pressure to publish many papers, as there

is today. Grant funding was relatively easy to obtain. Also, Dr. Ahrens had plenty of grant money because he was a highly respected scientist. Our research was never restricted by lack of funds. We were given considerable freedom in our research. Rockefeller had the tradition of using the “sink or swim” method of training young scientists. Nevertheless, the pace was comfortable, but stimulating through exchange with many brilliant people. The situation was almost ideal, and in many ways, more civilized than in the current competitive environment. WCR: How many PhD students were there in each class? SMG: About 20. WCR: You and Ahrens became very close? How much older than you was he? SMG: Eighteen years. We certainly had a close personal relationship, and a productive relationship. Pete was meticulous, demanding of excellence, and continuously questioning. New findings had to be confirmed in 3 or 4 different ways. For me, he was a terrific mentor, and he gave me a strong foundation in clinical research. WCR: Here, you went from Memphis, Texas, to Lubbock, to Houston, and then to New York City. Except for your 3-month sabbatical in Sweden, had you ever been out of Texas, or Oklahoma, before going to New York? SMG: On only a couple of occasions. WCR: New York must have been mind boggling. SMG: Indeed. Before going to the big and bad city there was considerable anticipation and anxiety, but it turned out to be a fabulous place to live. WCR: When did you get married? SMG: After my first year in medical school. WCR: How did you meet your wife? SMG: I met her first briefly at summer church camp during high school. In fact, I first knew her brother, Harry Parker. The Parkers also were Presbyterians, and they lived in Tulia, Texas, a small town between Amarillo and Lubbock, Texas. Harry had a sister, Lois Parker. Although I knew her for several years, both in high school and college, my relationship with her only began to grow during my senior year in college. WCR: So Lois went to Texas Tech, too? SMG: She did. WCR: What did Lois do while you were in medical school? SMG: She taught special reading classes in the Houston public schools. Except for the time when she was raising our young children, she has spent her whole adult life teaching children with reading handicaps. She followed a career similar to that of my sister, Elizabeth, and has brought an untold number of children up-to-speed academically, so that they could compete successfully with other children. WCR: When you went to New York, did you have any children? SMG: We had one 4-month-old girl, Pamela. She was born in Houston in 1962. WCR: How could you leave Rockefeller University, where each day you were with the world’s best scienINTERVIEW/SCOTT MONTGOMERY GRUNDY

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tists in an elegant place with good support? Your apartment was only a few blocks away, and there were great cultural opportunities and great professional stimulation. How did it come about that you went to Arizona? SMG: Often I have asked myself this same question, but it was quite clear that several factors influenced me. Even though Rockefeller was a wonderful place to do research, its commitment to clinical investigation seemed limited. Clinical research at Rockefeller had gradually given way to basic research. Therefore, I came to believe that opportunities for clinical investigation would probably be greater in other institutions. I made an attempt to obtain a joint appointment with Cornell Medical school, but was unsuccessful. Rockefeller at that time, and maybe even now, although located side-by-side with Cornell, did not have much interaction or communication. Each maintained its institutional separateness. Other factors in my decision included the relatively low pay for research physicians and concerns about supporting and educating a family in New York City. WCR: But what led you to Phoenix? SMG: The Phoenix offer grew directly out of my research. In our cholesterol balance studies we found that people who took the triglyceride-lowering drug, clofibrate, excreted excessive amounts of cholesterol from the body. We therefore inquired about the mechanism and speculated that the excess cholesterol probably came through the liver and into the bile. I thought it would be important to prove this, so I developed a method to measure amounts of cholesterol passing through the biliary tree. It required passing a triplelumen tube into the duodenum and using markers to estimate cholesterol flow from the bile into the duodenum. We found that patients taking clofibrate indeed had an excess of biliary cholesterol. About the same time, Dr. Donald Small in Boston made a seminal observation. He reported that people with cholesterol gallstones had what he called “supersaturated” or “lithogenic” bile (i.e., bile that carried more cholesterol than could be held in stable solution by the solubilizing lipids— bile acids and phospholipids). This discovery put the study of cholesterol gallstones on a scientific basis. Most gallstones are made out of cholesterol. It occurred to me that I could actually determine what causes lithogenic bile by measuring all of the lipids being secreted into bile. If so, I potentially could determine the causes of cholesterol gallstone formation. At Rockefeller, I perfected the technique of measuring biliary lipid secretion. At the same time, it was discovered that a high proportion of all Pima Indians in Arizona developed cholesterol gallstones. The institute of NIH, now called the National Institute of Diabetes, Digestive Diseases, and Kidney (NIDDK), had decided to build a research facility in conjunction with a new referral hospital for the Indian Health Service in Phoenix. Moreover, the gastroenterology community was putting more pressure on NIH to have more research in their field. In part to placate this community, I suppose, it was decided to put more emphasis on the 232 THE AMERICAN JOURNAL OF CARDIOLOGYT

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gallstone problem of the American Indians. NIDDK therefore built a 20-bed metabolic ward and a large laboratory facility on the top floor of the new facility. Dr. Robert Gordon, Clinical Director of NIDDK, offered to make me director of this new facility, provided I would concentrate on the gallstone problem. Enthusiasm for this project of course was an outgrowth of the work of Donald Small’s work on lithogenic bile, but it also was prompted by the observation of Reno Vlalachivc and Leon Swell that Navajo Indians had a reduced pool size of bile acids. I believe that Donald Small is the person who recommended me to Bob Gordon. Because my future at Rockefeller seemed problematic, I felt this was a good opportunity to apply my new method for measuring biliary lipid secretion. I was offered the position of section chief, which Bob Gordon told me was equivalent to being a full professor. Whether this is true or not, I don’t know, but I was ready to believe it. Anyway, I believe my decision was the right one. I took full advantage of the opportunity. The facility in Phoenix was outstanding. We had a research budget of 2 million dollars a year for research projects, and I have never had so much research money since. WCR: What did you discover in Phoenix? SMG: We found out why Indians develop gallstones. They have two defects in their biliary lipid metabolism. First, they oversynthesize cholesterol and pour this excess cholesterol into bile. This overproduction of cholesterol is secondary to obesity, which is common in Pima Indians. In addition, American Indians have an inherent defect in the regulation of bile acid synthesis that leads to a reduced pool of bile acids in the enterohepatic circulation. Thus, being overweight combined with a bile acid defect causes highly lithogenic bile and accounts for the high prevalence of gallstones. I was particularly proud of the fact that I discovered why American Indians in particular and obese people in general develop gallstones. This provides a physiological explanation for the long-known clinical phenomenon: fat, forty, female, and gallstones. The research also was a paradigm for our subsequent findings that the metabolic stress imposed on a background of latent genetic defects elicits various clinical metabolic disorders. WCR: So you were in Phoenix 2 years? You really did a lot in those 2 years? SMG: I was prepared for it. WCR: Did you ever go home during those 2 years? SMG: Not too often. We really worked hard. There was not a lot to do in Phoenix but work. We had a good team. NIDDK made a big investment there. WCR: How many people did you have in that operation? SMG: Four or 5 physicians. WCR: You went to San Diego-La Jolla, California, in January 1973? SMG: I would have been happy to have stayed in Phoenix because of the facilities and the opportunity. Shortly after I went to Phoenix, however, Dr. Daniel Steinberg, who had recently gone to the new medical school in San Diego, asked me if I would be chief of JANUARY 15, 1999

the metabolic section at the Veterans Affairs (then called Veterans Administration) Hospital, which was on the campus of the University of California, San Diego (UCSD). I told him that his offer was attractive, but I had just started in Phoenix. Dan said the VA Hospital was not completed, and he would hold the position for a couple of years. I visited and found La Jolla and UCSD to be terribly attractive. La Jolla is a beautiful city. Also, there was a terrific faculty at UCSD. Eugene Braunwald was chairman of Medicine there, and he had robbed the NIH of some of its best investigators when he set up the Department of Medicine. It did not take a lot of persuading for me to realize that even though Phoenix was a wonderful research opportunity and offered the chance to put my research on the map, it did not compare with San Diego as a place to build an academic career. I therefore moved to San Diego in 1973. WCR: How did it work out? SMG: Everything worked out very well. UCSD was a fine medical school. The only problem was a limitation in resources. The VA Hospital was cramped for research space, and this curtailed expansion of my research program. Also, potential sources of funding were limited mostly to NIH grants. I certainly am not complaining, however. The facilities were adequate, and we accomplished much research and published a large number of papers. The VA Hospital provided me with a metabolic unit that must have been one of the best in the country. We were able to keep up to 20 patients on that ward, which allowed us to carry out several studies simultaneously. WCR: It sounds like you kept patients on the metabolic ward for months if you wished? SMG: We could keep them as long as we wanted. The opportunities seemed unlimited. All my time in San Diego was satisfying. Overall, the medical school was outstanding. I had the chance to interact with many outstanding professors. Also, I was able to develop a close and wonderful relationship with Dan Steinberg. He was one of the giants in the lipid field, a tremendous associate, very supportive of me, and a great friend. I have nothing negative to say about my relationships at the VA Hospital or UCSD. WCR: Tell me about your research in San Diego. SMG: One phase of our research was on the metabolism of cholesterol and bile acids. I continued to study the mechanisms of formation of lithogenic bile and cholesterol gallstones. This work was done in association with research fellows and faculty colleagues. These included Henry Mok, Klaus von Bergmann, and Gary Hardison. Also, my associate from Rockefeller days, Alan Hofman, moved from the Mayo Clinic to UCSD, and we frequently discussed research issues. I believe that our research provided several new insights into the enterohepatic circulation of cholesterol and bile acids in humans. In particular, we better defined the influence of obesity on biliary lipid metabolism. At this time I also became involved in the National Cholesterol Gallstone Study, a multicenter trial to determine whether chenodeoxycholic acid would effectively dissolve cholesterol gallstones.

The study was headed by Dr. Leslie Schoenfield of Los Angeles, and was a model of a clinical trial. Although the trial was clinically negative, it engendered new approaches to the clinical management of gallstones. WCR: You also worked on the blood lipids, didn’t you? SMG: Yes. We did many studies on the mechanisms of hypertriglyceridemia in humans. It appeared that most patients at the VA Hospital had elevated serum triglycerides. This observation led us to develop methods to determine rates of formation and catabolism of triglyceride-rich lipoproteins in humans. These methods required use of radioisotopes and we developed kinetic models to decipher metabolic parameters. In this effort, I collaborated with Dr. Virgil Brown and Dan Steinberg. Also, our team worked closely with investigators at NIH in Bethesda, Drs. Mones Berman and Loren Zech, as well as with Dr. Barbara Howard in Phoenix. Investigators in my own laboratory who worked on these problems included Drs. Antero Kesaniemi and Gloria Lena Vega, among others. At this time, I also developed collaborative studies with Drs. David Bilheimer, Fred Dunn, Joseph Goldstein, and Michael Brown at the University of Texas Southwestern Medical School. These collaborative metabolic studies probably paved the way for my move to Dallas. All in all, I believe our studies on metabolism of lipoproteins helped to define pathways and regulation of serum lipoproteins in patients with different forms of hyperlipidemia. In my view, our major observation in San Diego was that obesity leads to an overproduction of lipoproteins by the liver, and when obesity is combined with hereditary defects in catabolism of VLDL and LDL, patients will develop hypertriglyceridemia or hypercholesterolemia, respectively. It reinforced our paradigm of the interaction of obesity and genetics in the causation of metabolic disorders. WCR: What about your nutrition studies in San Diego? SMG: In this area I was fortunate, because I had the opportunity to work with Dr. Fred Mattson. Fred had been director of lipid research at Proctor and Gamble (P&G) for many years. I knew him from my Rockefeller days. He retired at an early age from P&G and moved to San Diego, where he became director of the Lipid Research Clinic laboratory at UCSD. Fred and I came up with the idea that monounsaturated oils (like olive oil) might be superior to polyunsaturated oils in lowering serum cholesterol levels. So we designed a study to test this hypothesis. I completed the study after I moved to Dallas. WCR: You found that monounsaturated fatty acids are in fact better for us than polyunsaturated fatty acids? SMG: Overall, they seem to be safer and just as effective. WCR: Effective in lowering LDL? SMG: Yes, our results indicated that they are as effective in lowering LDL. Also, they do not lower HDL, as polyunsaturates do when consumed in large INTERVIEW/SCOTT MONTGOMERY GRUNDY

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amounts. There has been a long-term concern that excess polyunsaturated fatty acids might have detrimental effects, for example, promoting cancer, suppressing the immune system, and facilitating LDL oxidation. We believed that we circumvented these problems by going to monounsaturates. This form of unsaturated fatty acids has been consumed in large amounts as olive oil for centuries in the Mediterranean area. In Mediterranean countries, there is a low incidence of coronary heart disease, as shown by the 7-Country Study, as well as a low rate of cancer. We believed that there was a lot going for monounsaturates. WCR: If you are going to have to eat eggs, cook them in olive oil? SMG: If you are going to use fat in your diet, monounsaturates are the best kind. WCR: Do you eat a lot of olive oil in your home? SMG: We eat some. I don’t use huge amounts of fat and oil, but olive oil is my favorite. WCR: Why is olive oil so expensive? SMG: Olive oil is expensive because of its taste and limited supply. Olive trees grow only in certain small areas of the world. Costs are increased more by the expense of production, preparation, and shipping. However, there are other sources of monounsaturates: canola oil and high-monounsaturated forms of safflower oil and sunflower oils. Later, when I was in Dallas, I worked with animal scientists at Texas A&M University to produce pork that was rich in monounsaturates. WCR: When you say polyunsaturates, what you in essence are saying is that the dominant component of that particular fatty acid is the polyunsaturated component. Some saturated and monounsaturated components are also there, but they are in the minority. SMG: Yes. Olive oil is roughly 75% monounsaturated. Our study has proved to be controversial, but we believe that monounsaturates are the best of the 3 fatty acids. The idea that polyunsaturates are the best, which was the predominant dogma in the 1960s and 1970s, has not fallen easily. Even much of my own research has been devoted to understanding how polyunsaturates lower cholesterol levels. However, it is now my opinion that we should limit intakes of polyunsaturates. We require small amounts in the diet, but not large amounts. WCR: If you give 100 people a fatty acid that is predominantly polyunsaturated or monounsaturated, you will lower the LDL in a lot of them, but in some of them, you don’t lower it at all. Is that correct? SMG: If you control exactly what a person consumes on a metabolic ward, and you replace saturated with any type of unsaturated fatty acid, either poly or mono, most people will lower their LDL levels to some extent. However, the degree of lowering is quite variable. The reduction will range from 10% to 30%. Dr. Margo Denke, who has worked with me in Dallas, has done extensive research on the variation in diet responsiveness, and continues to work on this important issue. WCR: How do saturated fatty acids raise our LDL? 234 THE AMERICAN JOURNAL OF CARDIOLOGYT

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SMG: That is a question that goes back to the beginning of my research with Pete Ahrens. We phrased the question differently in those days. We asked, “How do polyunsaturated fatty acids lower the cholesterol level?” That was the focus of our thinking then. It is generally now believed that saturated fatty acids raise the LDL levels, whereas other nutrients (polyunsaturates, monounsaturates, and carbohydrates) yield a “baseline” LDL level. These later nutrients do not actually lower LDL levels like cholesterol-lowering drugs. We still don’t know the answer to this question from a biochemical viewpoint. The best evidence, however, suggests that saturated fatty acids suppress LDL-receptor synthesis, whereas other nutrients allow for a “normal” expression of receptors. Dr. John Dietschy and his group in Dallas have extensively studied this pathway in animal models. WCR: You must have loved living in La Jolla? Here you have lived in Memphis, Texas, Lubbock, Texas, Houston, Texas, New York City, Phoenix, Arizona, La Jolla, California, and now somebody is knocking on your door to return to Texas. How did that come about? SMG: Let me say that every move for me opened new doors and reinvigorated me. Each had a highly positive effect on me. The opportunity to come to Dallas was just plain good luck for me. There were influential people in the Dallas community who thought that medical schools are not paying enough attention to nutrition. They felt that the University of Texas at Southwestern in particular should teach medical students and young physicians more about nutrition, because good nutrition offers the best approach to preventing disease and prolonging life. Bill, I know that you hold this belief strongly yourself. Anyway, these people began to work on the medical school to try to get it to start a nutrition program. WCR: Who were the people? Have they been the big donors to the University of Texas Southwestern? SMG: That is what many of them are now. I might try to create a bit of history. The central persons are Mr. Peter O’Donnell, Jr. and his wife, Edith O’Donnell. They deserve enormous credit, not only for creating the nutrition program, but in addition for much of what Southwestern is today. They are primarily responsible for the creation of the Center for Human Nutrition, and I was fortunate to be chosen to be its first director in 1981. The O’Donnells made the initial endowment to the Center for Human Nutrition. The decision to create this Center was made by Dr. Kern Wildenthal, then dean of Southwestern, and Dr. Charles Sprague, Southwestern’s president. The people who suggested my name to be the director of the Center were Drs. Joseph Goldstein and Michael Brown, who as everyone knows, work in the cholesterol field, too. At the time I came to Southwestern, they had already discovered the LDL receptor and were on their way to fame. The discovery of the LDL receptor is the most important discovery ever made in the lipoprotein field, and it rightly entitled Goldstein and Brown to the Nobel Prize in 1985. I believe that they thought I would bring good science to the Center JANUARY 15, 1999

Dr. Gloria Lena Vega is carrying out research on obesity and fatty acid metabolism and their role in hypertriglyceridemia. Dr. Kenny Jialal has developed a large program in antioxidants and their role in prevention of chronic disease. Dr. Margo Denke is working on the genetic and environmental basis of variation in diet responsiveness. Dr. Abhimanyu Garg is making seminal observations on genetic disorders of adipose tissue that may provide new insights into the problem of insulin resistance. Dr. Jonathan Cohen has started a large program in the study of human genetics and its interface with nutrition, particularly obesity. He has recently made key observations on genetic facFIGURE 7. SMG (far right) with Peter O’Donnell, Jr. (far left), Mary Ann Cauldwell tors controlling HDL levels. Dr. Shailesh (center left), and Carolyn Bacon (center right). Patel has recently uncovered the genetic locus of a rare but important disorder in for Human Nutrition, which was to be devoted to cholesterol metabolism. Dr. Nilo Cater is studying the human research. In addition to these influential peo- effects of new nutritional approaches to lowering LDL ple, Dr. Ronald Estabrook has been a strong supporter levels, and Dr. Nicola Abate is investigating the of our Center. Also, the Veterans Affairs Medical genetic basis and metabolic consequences of insulin Center in Dallas made a major commitment to our resistance, particularly as they are related to abnorprogram by creating a metabolic ward for me to carry malities in fat distribution. All of our faculty memout clinical investigation. bers are the mentors of research fellows who are Also, I must mention that many influential people being trained in our Center. My job now is to guide in Dallas have been strong moral and financial sup- and support this sizable group of creative scientists, porters of our program. Mr. O’Donnell, in his wisdom, both faculty and research fellows. established a support group named the Friends of the WCR: How many people do you have in the Center Center for Human Nutrition. This group consists of for Human Nutrition? almost 200 individuals or families in the Dallas area SMG: We have 8 faculty, at least an equal number who are committed to yearly contributions to our or more of research fellows, along with technicians, Center. This group has been lead by such people as nurses, dietitians, and administrative assistants, for a Vin Prothro, Charles Best, Carla Francis, Margo Perot, Lida Hill, and Rita Clements, Roger Horchow, total of about 35. WCR: When you started to medical school in 1955, Carolyn Bacon, and Dr. Philip Montgomery, just to name a few. Their support has provided a major fi- you started right away investigating atherosclerosis and you have continued investigating that problem nancial underpinning to our Center. WCR: How does the Center for Human Nutrition fit your entire career. Here you come from an area of the world, Texas, where you were surrounded by cows. I into Southwestern Medical School? SMG: It provides space and financial resourses for bet your daddy had cows on the farm. SMG: Yes. That is right. We even had a cow in faculty members who are working in the field of town that I milked. nutrition and related areas. Its major thrust is human WCR: So you were surrounded by bovine muscle, research, and naturally I have turned its focus to cholesterol, lipids, lipoproteins, diabetes, and the pre- milk, butter, and cheese. Then you got into chemistry, vention of atherosclerosis. Our Center’s faculty mem- and it sounds almost like the day you hit medical bers have established collaborations with many other school or certainly the day you hit organic chemistry, investigators at Southwestern. We are very fortunate, that you started doing research. You have focused on because Southwestern Medical School is one of the the same problem for over 40 years. SMG: That is true. world’s foremost medical research institutions and it WCR: You have not dilly dallied here and yon; it provides a rich environment for collaboration. We also work closely with the Department of Clinical was straight ahead on the same problem. You are labeled as a endocrinologist? What do you consider Nutrition in the School of Allied Health Sciences. WCR: So you came to Dallas in 1981 at age 48. yourself? SMG: A metabolic nutritionist. How much longer are you going to work? WCR: The amount of training you had in internal SMG: For several more years, I hope. Right now, the Center for Human Nutrition is at the peak of its medicine was limited. (That was not infrequent when productivity. Several of the Centers’ faculty have ma- you and I came along.) Your residency training was a tured into independent investigators in their own right. small portion of your professional life. You were in INTERVIEW/SCOTT MONTGOMERY GRUNDY

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research right away. (Incidentally, Eugene Braunwald was the same way.) SMG: The same was true of many people who trained at Rockefeller and the NIH. Most have medical school positions and some are chairpersons of departments of medicine. I have always felt insufficient in my training in internal medicine. This probably has impaired my ability to teach on attending rounds. I have been conscientious in trying to improve my knowledge in internal medicine. Through my attending experience at UCSD and Southwestern, I have learned a great deal. WCR: How much time do you spend on attending rounds? SMG: Six weeks a year in general internal medicine. Also, I see a large number of patients in our lipid clinic and on the metabolic wards. WCR: You have really done an enormous amount of work during these 401 years. Of all of your contributions, which ones are you the most proud of? What work are you most pleased with? When you are gone, what do you want people to remember about you? SMG: In research, there are 3 areas. But first, let me say that since medical student days I have been working on the regulation of the blood cholesterol and lipoprotein levels. This has been the overriding theme of my research. I was convinced that abnormalities in lipoprotein metabolism and concentrations underlie much of the atherosclerotic process. WCR: What are the 3 areas? SMG: First, I am pleased with the work we have done to elucidate pathways of cholesterol and lipoprotein metabolism. Development of new techniques to study these pathways has been particularly gratifying. The most definitive first result of this effort was the discovery of the metabolic basis of cholesterol gallstone formation, which was the outgrowth of cholesterol balance methodology. It also established the paradigm of the interaction of obesity and genetics in causation of metabolic disorders. Second, I am perhaps best known for our research in dietary fat. The optimal intake of dietary fat is such an important public health issue and any new information is both welcome and influential. I have been particularly rewarded for clarifying the role of monounsaturated fat in the diet. This effort has been influential in modifying dietary fat recommendations around the world. Third, our group at Southwestern played an important role in the rejuvenation of the HMG CoA reductase inhibitors (statins) at the time when interest in these agents was dormant. The success of the statins in the treatment of hypercholesterolemia has been particularly satisfying. I might recount some of the interesting history of these drugs. This class of agent was discovered in Japan by Dr. Akira Endo, who was working for a pharmaceutical company. He discovered a drug, compactin, that lowered serum cholesterol in animals. Compactin then was shown to lower cholesterol levels in humans. Shortly thereafter, Merck followed the lead and developed a similar drug called mevinolin, now named lovastatin. Merck sci236 THE AMERICAN JOURNAL OF CARDIOLOGYT

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entists also showed that mevinolin lowered cholesterol levels. However, neither drug was advanced further in development at this time. When I moved to Dallas, Joe Goldstein and Mike Brown were interested in the statins because they activated LDL receptor synthesis. I had many conversations with them about these drugs. At this time, Merck was not committed to developing mevinolin, and there were rumors that compactin caused cancer in animals. Moreover, conventional wisdom among drug companies was that cholesterol-lowering drugs were not financially viable. There was one person at Merck, however, who was convinced of lovastatin’s potential. This was Dr. Jonathan Tobert. I was able to work out an arrangement with Jonathan and Merck, such that I could apply for an IND (Investigational New Drug) from the FDA (Food and Drug Administration) to test lovastatin in humans. I got the IND and Merck provided us with the drug. This was 1982. Another investigator, Dr. Roger Illlingworth, from Portland, Oregon, had a similar arrangement. Dr. David Bilheimer and I tested lovastatin in hypercholesterolemic patients and found it to be extremely effective in lowering serum cholesterol levels. Goldstein and Brown were intimate advisors in these studies. We published our findings in 1983. Goldstein and Brown and others at Southwestern were influential in renewing interest in the statins at Merck. Thus, in my view, the Southwestern team played an important role in promoting the statins at a time when their future was in question. Subsequently, researchers in the Center for Human Nutrition did many different studies that revealed new, potential uses of statins in different forms of hyperlipidemia. Now, everyone knows how beneficial the statins are. They are being used in millions of people worldwide. Naturally, it is highly rewarding to have meaningfully participated at the beginning with these agents. WCR: This is a situation where you had to convince the pharmaceutical company rather than the pharmaceutical company’s trying to convince a group of physicians? SMG: That is probably true. That, at least, is my perspective. You could talk to people at Merck and perhaps get a different perspective. Certainly, the person who bit the bullet at Merck was its chairman, Dr. Roy Vagelos. He is the one who took the financial gamble and he deserves an enormous amount of credit, going out on a limb and committing Merck to lovastatin at a time when it was not clear whether it would be profitable or not. I do, however, believe that the scientific work combined with enthusiasm from Southwestern was a significant factor in promoting the further development of this class of drugs. Whatever my contribution, the statins represent the greatest advance in line with my quest for better ways to regulate serum lipoprotein levels. Of course, other investigators have been seeking this holy grail. These lipoprotein investigators, starting with John Gofman and his associates, in truth, have been a small band of committed researchers with a dream that has been largely realized by the great advances of the past decade. JANUARY 15, 1999

WCR: You are talking about your most important contributions. You have named 3. Can you discuss your statemanship and education endeavors and treatment stands you have been involved in? SMG: This has been a gradual but increasing effort, starting first with the American Heart Association. In the early 1980s, I was the chair of the Nutrition Committee of the American Heart Association. In 1982, we produced a rationale statement for the American Heart Association’s dietary recommendations. I was the senior author in this report, which set forth clearly the American Heart position about diet. I have continued to work with the American Heart Association ever since and have been chairperson of several committees: Cholesterol Task Force, Task Force on Risk Reduction, Prevention Committee, Arteriosclerosis Council, and Council on Scientific Councils. These committees have put out a series of statements on nutrition, treatment of hyperlipidemia, and other risk reduction strategies. In 1986, I was appointed as the American Heart Association’s representative to the newly formed National Cholesterol Education Program (NCEP) of the National Heart Lung and Blood Institute. I have participated one way or another in all of the NCEP’s panel reports. I was chairperson of the second NCEP Adult Treatment Panel report (ATP II), which made recommendations for treatment of high blood cholesterol in adults. I have tried to be a spokesman for NCEP. Working on NCEP with Dr. James Cleeman, director of NCEP, and Claude Lenfant, Director of NHLBI, has been a joy. It also has been satisfying to me, because I believe that the NCEP and its affiliated organizations, including the American Heart Association, have had a major impact on the way people think about cholesterol. I recognize that the science underpinning of the cholesterol hypothesis has improved progressively in recent years, and this has helped to convince people about the importance of cholesterol in atherosclerosis, but science is not always immediately translated into clinical practice. For this reason, a lot of us, including yourself, Bill, promote cholesterol awareness and understanding through lectures and position papers. I sense that these efforts do have a major effect on attitudes about cholesterol and nutrition. WCR: Dr. Grundy, you have done a lot of work on triglycerides. I am sure you get the question a lot, “How important are triglycerides?” It seems to me that since your recommendations from the Adult Treatment Panel that the major focus should be on LDL cholesterol, you have had a lot to say about triglycerides. I wonder if you are changing your tune a bit on triglycerides? SMG: I still believe that priority should be given to LDL. LDL is the major atherogenic lipoprotein. Recent clinical trials bear out the benefit of LDL lowering. However, I do believe that the whole triglyceride area is very important. Our research has shown that high triglyceride levels are largely due to the interaction of obesity and latent genetic defects in triglyceride catabolism. There is growing evidence that trig-

lyceride-rich lipoproteins are atherogenic, similar to LDL. Moreover, high triglycerides are a good clinical indicator of insulin resistance, and insulin resistance is going to emerge as another major risk factor for heart disease. Also, high triglycerides usually are associated with low HDL cholesterol and small, dense LDL, both of which appear to be atherogenic factors. Therefore, high triglycerides are linked to atherogenesis through multiple pathways. It is a mistake for clinicians to ignore elevated triglycerides, but the clinical focus should be on associated risk factors as much as on high triglycerides, per se. WCR: What about measuring non-HDL cholesterol (total cholesterol minus HDL)? How does that fit versus having to have a fasting sample so you get a triglyceride value? SMG: We have been interested in the idea of combining LDL and VLDL into a single number, which is non-HDL. If VLDL is atherogenic like LDL, it seems reasonable to combine the two and let that be the target of treatment. However, some investigators feel that this takes the focus off LDL, which has been espoused by NCEP as the primary target of cholesterollowering therapy. Thus, for clinical purposes, it may be necessary to continue to separate LDL and triglycerides (or triglyceride-rich lipoproteins). LDL should still be the primary target of hyperlipidemia treatment, whereas elevated triglycerides can be managed separately. WCR: What is your day-to-day life like now? I know you spend a lot of time over here at work. What time do you get up in the morning? What time to do you go to bed at night? Can you describe a typical day? SMG: I usually get up about 6:30 A.M., do a little exercise, and read The New York Times and The Dallas Morning News, and get to work around 9:00 A.M. Often, I go to the VA Hospital directly from home and check on our activities there or see patients in the lipid clinic. Then I come to the medical school and try to work with the faculty on their plans, their research designs, their fundraising efforts, their manuscripts. This, plus correspondence and working on manuscripts, take up most of the afternoon. I spend considerable time with NCEP and the American Heart Association business, and this requires a lot of telephone work. Finally, I usually spend a couple of hours doing paperwork at home at night. WCR: What time do you leave the medical school? SMG: Between 7:00 and 8:00 P.M. WCR: So you are putting in about 10 to 11 hours at work? Then, you put in another couple of hours at home. What time to you go to bed? SMG: Eleven o’clock. WCR: So you get a reasonable night’s sleep? SMG: Yes. I am not like Dr. DeBakey, who seemingly sleeps only about 4 hours. I wish I could do that, but I cannot. WCR: What about Saturdays and Sundays? Do you come in? SMG: Yes. I usually come to my office at 11:00 A.M. on Saturday and Sundays and work until 6:00 P.M. It might seem that I am a slave to work, but my INTERVIEW/SCOTT MONTGOMERY GRUNDY

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work schedule is frequently interrupted by trips. I travel frequently to Washington for committee meetings (the NCEP and the Food and Nutrition Board), to the American Heart Association, for lipid symposia (like you do, Bill), and on visiting professorships. It is not unusual for me to be gone a couple of days a week. WCR: How many trips do you go on a year? SMG: Too many. I would say probably 25 or 30. WCR: Do you have hobbies outside of medicine? SMG: I would call them interests more than hobbies. I have a great interest in history and biography, and I read on these subjects every chance I get. I know a lot more about them than you might think. I used to read a good deal in the areas of general science, psychology, and philosophy, but my current interests are in history and politics. One of my “hobbies” is preparation for attending rounds by studying internal medicine. I do this to try to overcome by deficit in clinical training. I have developed a system of cards with case histories that I use for teaching medical students. In my attending periods, I try to spend extra time with the students alone. WCR: Although you went to college on an athletic scholarship, now you don’t play golf, tennis, or run? SMG: I don’t run. I walk and exercise at home, but don’t participate in sports. I do occasionally watch sports on television, but I seem to have gotten the playing of competitive sports out of my system when I was young. WCR: You have how many children? SMG: Two, a daughter and a son. WCR: Pamela and Stephan? I know Pamela has written a book, because I have seen 1 of them. What does she do? SMG: Pamela went to Yale for college. She then worked as a journalist in Anniston, Alabama, for a couple of years. While in Anniston she conducted oral history interviews in a small, rural county. Her study, entitled You Always Think of Home: A Protrait of Clay County Alabama (University of Georgia Press, 1991), presented a Studs-Terkel style oral portraits of several dozen county residents. Then she left Alabama and entered graduate school at the University of North Carolina at Chapel Hill. Her PhD dissertation, Learning to Win, looked at the development of high school and college sports programs in North Carolina during the twentieth century. This thesis explored the way athletic competition became an integral part of the American educational system, and a key component of American culture. It describes the links that sports supporters drew between athletic programs and visions of a changing society. Pamela considered the roles that sports has played in creating communities, shaping ideas about men and women, and influencing the course of racial integration. Her thesis recounts several key moments in a heated and century-long debate over the direction and purpose of school athletics and how these debates reflect larger differences that are shaping American society. WCR: Is Pamela an athlete? SMG: She played tennis in high school, but not too much since. 238 THE AMERICAN JOURNAL OF CARDIOLOGYT

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WCR: What about your son? SMG: Stephan is very literary and has written sev-

eral books. He went to Southern Methodist University for college, and then to Cambridge University for his PhD. He is an expert on Germanic and Norse literature, legend, and society. His books generally take the form of historical novels or recounting of Germanic legends. They have been translated into German and are widely sold in Germany, England, and other European countries. They also are read in the United States. Stephan now lives in Ireland, which gives him ready access to European countries for his continuing research. WCR: How did Stephan get interested in these areas of study and writing? SMG: He has been reading and writing stories since he was very small. His Scandinavian heritage (on his mother’s side) seemingly led him to an interest in the culture and religion of the Vikings, which in turn inspired him to retell the great stories of the North in his novels. WCR: What do you want to do for the rest of your professional career? SMG: I am extremely interested in research questions that we are currently addressing in the Center for Human Nutrition. My major interest right now is on “atherogenesis beyond LDL.” A lot of the LDL problem we now understand and have largely solved, but I believe that other metabolic factors promote atherogenesis beyond an elevated LDL. One of these is the oxidation of LDL, which is the major interest of my colleague, Dr. Kenny Jialal. Other atherogenic factors are related to triglycerides, HDL, and insulin resistance. Most of the faculty members of the Center for Human Nutrition are working in one form or another on metabolism and genetics of lipoprotein and their relation to obesity, insulin resistance, and diabetes. I subsume this thrust under the term metabolic syndrome. This syndrome consists of the coexistence of multiple metabolic risk factors (dyslipidemia, hypertension, glucose intolerance, and a coagulation defects) in a single individual. I want to continue my efforts to better understand the origins and management of the metabolic syndrome. In my opinion the metabolic syndrome represents the product of the interaction of genetics and acquired factors. WCR: I guess you were behind the NIH’s push to lower the body mass index to define obesity? SMG: That is partly true. Most doctors don’t even know what body mass index is. I was on an NIH panel that just put out recent treatment guidelines on obesity. These have been controversial because some investigators have said that we are classifying almost all Americans as obese. In truth, there is an extremely high prevalence of obesity in the United States. All of our research tells us that even mild obesity when combined with latent genetic defects leads to several cardiovascular risk factors (the metabolic syndrome). Therefore, physicians need to make a mental link between excess body fat and cardiovascular risk. Control of obesity is the best way to reduce several cardiovascular risk factors at once. JANUARY 15, 1999

WCR: What is your body mass index? SMG: It is about 23. We call overweight a body

mass index of 25 or greater. At this level the vast majority of people, except for a few muscular people, have excess body fat. However, another way to assess obesity is to measure the waist circumference. A large waist circumference is closely associated with insulin resistance and the metabolic syndrome. WCR: Why did the NCEP take obesity off the last list of risk factors? SMG: This requires a little explanation. Obesity is an important cause of all the metabolic risk factors like insulin resistance, hypertension, high triglyceride, high LDL, low HDL, and coagulation disorders. These are considered the primary risk factors and the effects of obesity on risk are largely mediated through these factors. Therefore, counting obesity per se as a risk factor may actually be counting it twice. Nonetheless, obesity is the underlying cause of several risk factors and, hence, is a contributing cause of cardiovascular disease. Obesity itself should be a direct target for treatment. This explains why the NIH has produced a separate guideline on the clinical management of obesity. WCR: You were the editor of the Journal of Lipid Research for 5 years. Did you enjoy that? SMG: It was a lot of work. Being editor is a rather thankless task in many ways. You make quite a few authors unhappy when you reject their papers. Still, it is stimulating and helps to keep you up to date. I felt that taking on the task was my responsibility to the lipid field, and particularly because Pete Ahrens was one of the founders of the journal. To me, becoming editor was some kind of obligation. WCR: What if somebody came along and offered you a deanship of a medical school? You have kept straight ahead with your research and have not been diverted off course. Are you ever tempted by other offers? SMG: I am just committed to my kind of research, and I do not intend to be diverted. It’s as simple as that. First of all, I have built up a lot of experience in this area, and I can still apply that experience. This is particularly the case in helping younger investigators to develop their careers. I can do this job better than I could as being a dean. Other people are better qualified and trained for such positions. WCR: What advice do you give new, young researchers if they want to a career in medical research? SMG: My advise is “do it.” Although we have been through some tough times with managed care and cutbacks in research funding, the future looks brighter. The country seems to be coming to the realization that we need a strong medical research base and the future of the health of the nation is going to depend on that, so there will be opportunities now. I would like to make a special comment about clinical investigation as part of the medical research effort. I have the strong feeling that academic medicine does not put enough emphasis on clinical research. It is easier for faculty to advance academically

doing basic science research than in clinical investigation. This is a mistake. Everyone agrees that medical practice should be evidence based. Evidence is derived from 4 types of research: basic research, epidemiology, clinical investigation, and clinical trials. Basic research provides the raw material for medical practice. Clinical investigation takes this knowledge and tests its potential application in patients. Finally, clinical trials test promising applications in large numbers of patients. Overemphasis on basic research at the expense of clinical investigation in medical schools creates an imbalance that impairs the full development of information required for evidence-based medicine. To a large extent, both medical schools and the NIH have abrogated their responsibilities in clinical research and clinical trials and have turned them over to the pharmaceutical industry. Although this industry has the responsibility to perform objective trials, its control of the funding and scientific questions leaves important gaps in our knowledge that can only come from extensive academic involvement in clinical research. One of my aims is to help to reestablish the balance in medical schools between basic research, clinical investigation, and clinical trials. WCR: As you look back, have you made any mistakes in your several moves, or have you spent too much time in one line of research that in retrospect you wished you had gone down another road? SMG: Perhaps the fundamental irreversible decision in my career was to do clinical research rather than basic research. Once that fundamental decision was made, it determined the course of my work. If I had chosen basic research, my career undoubtedly would have been totally different. I fully realize that there is a strong prejudice in the academic world in favor of basic research over clinical research, and I have paid a price in prestige. However, this disadvantage has been offset for me by my conviction that the academic world must seek a balance between basic and clinical research. Anyway, I can only guess at how my career might have been different if I had chosen basic research. I might have discovered something important, or perhaps I would have fallen by the wayside out of discouragement. I don’t know. WCR: Is there anything, Dr. Grundy, you would like to discuss before we stop? SMG: I want to emphasize again how important my colleagues have been in supporting my career. I have not mentioned many associates whose names are on our joint papers, although their names will be listed in the bibliography that accompanies this interview. In addition, there have been a couple of people who have worked with me for many years who deserve special mention. Marjorie Whelan has been a long-term colleague and advisor. She was enormously helpful in establishing the metabolic units in Phoenix, San Diego, and Dallas. In Dallas, she has been the clinical coordinator of the Center for Human Nutrition, and she has been a vital interface with our patients, medical school administration, and donors. Her long-term contributions to our program have been tremendous. Another person who has given energy and stability to INTERVIEW/SCOTT MONTGOMERY GRUNDY

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our research efforts is Dr. Gloria Lena Vega. She was the only scientist who moved with me from San Diego to Dallas, and she has contributed to every phase of the Center’s work. I hope that this discussion makes clear that whatever accomplishments in the research area and public policy are attached to my name represent a team effort. I have been fortunate to be the spokesman for much of this united effort, but in no way should I be given primary credit for it. WCR: Scott, I want to thank you for sharing yourself and your thoughts with the readers of The American Journal of Cardiology. I appreciate your being so open. SMG: It was my pleasure.

SMG’S BEST PUBLICATIONS AS SELECTED BY HIM 6. Grundy SM, Griffin AC. Effects of periodic mental stress on serum cholesterol

levels. Circulation 1959;19:496 – 498. 7. Grundy SM, Griffin AC. Relationship of periodic mental stress to serum

lipoprotein and cholesterol levels. JAMA 1959;171:1794 –1796. 13. Grundy SM, Ahrens EH Jr, Miettinen TA. Quantitative isolation and gasliquid chromatographic analysis of total fecal bile acids. J Lipid Res 1965;6:397– 410. 14. Miettinen TA, Ahrens EH Jr, Grundy SM. Quantitative isolation and gasliquid chromatographic analysis of total dietary and fecal neutral steroids. J Lipid Res 1965;6:411– 424. 15. Spritz N, Ahrens EH Jr, Grundy SM. Sterol balance in man as plasma cholesterol concentrations are altered by exchanges of dietary fat. J Clin Invest 1965;44:1482–1493. 16. Grundy SM, Ahrens EH Jr. An evaluation of the relative merits of two methods for measuring the balance of sterols in man: isotopic balance vs. chromatographic analysis. J Clin Invest 1966;45:1503–1515. 17. Grundy SM, Ahrens EH Jr, Salen G. Dietary beta-sitosterol as an internal standard to correct for cholesterol losses in sterol balance studies. J Lipid Res 1969;9:374 –387. 18. Grundy SM, Ahrens EH Jr. Measurements of cholesterol turnover, synthesis and absorption in man, carried out by isotope kinetic and sterol balance methods. J Lipid Res 1969;10:91–107. 19. Grundy SM, Ahrens EH Jr, Davignon J. The interaction of cholesterol absorption and cholesterol synthesis in man. J Lipid Res 1969;10:304 –315. 21. Grundy SM, Ahrens EH Jr. The effects of unsaturated dietary fats on absorption, excretion, synthesis, and distribution of cholesterol in man. J Clin Invest 1970;49:1135–1152. 26. Grundy SM, Ahrens EH Jr, Salen G, Schreibman PH, Nestel PJ. Mechanism of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia. J Lipid Res 1972;13:531–551. 29. Grundy SM, Metzger AL. A physiological method for estimation of hepatic secretion of biliary lipids in man. Gastroenterology 1972;62:1200 –1217. 30. Grundy SM, Metzger AL, Adler R. Mechanisms of lithogenic bile formation in American Indian women with cholesterol gallstones. J Clin Invest 1972;51: 3026 –3043. 32. Metzger AL, Adler R, Heymsfield S, Grundy SM. Diurnal variation in biliary lipid composition: possible role in cholesterol gallstone formation. N Engl J Med 1973;288:333–336. 33. Grundy SM, Duane WC, Adler RD, Aron JM, Metzger AL. Biliary lipid outputs in young women with cholesterol gallstones. Metabolism 1974;23:67–73. 34. Adler RD, Metzger AL, Grundy SM. Biliary lipid secretion before and after cholecystectomy in American Indians with cholesterol gallstones. Gastroenterology 1974;66:1212–1217. 36. Grundy SM. Effects of polyunsaturated fats on lipid metabolism in patients with hypertriglyceridemia. J Clin Invest 1975;55:269 –282. 37. Bennion LJ, Grundy SM. Effects of obesity and caloric intake on biliary lipid metabolism in man. J Clin Invest 1975;56:996 –1011. 38. Bilheimer DW, Goldstein JL, Grundy SM, Brown MS. Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia. J Clin Invest 1975;56: 1420 –1430. 39. Grundy SM, Mok HYI. Chylomicron clearance in normal and hyperlipidemia man. Metabolism 1975;25:1227–1239. 43. Grundy SM, Mok HYI. Colestipol, clofibrate and phytosterols in combined therapy of hyperlipidemia. J Lab Clin Med 1977;89:354 –366. 44. Grundy SM, Mok HYI. Determination of cholesterol absorption in man by intestinal perfusion. J Lipid Res 1977;18:263–271. 45. Bennion LJ, Grundy SM. Effects of diabetes mellitus on cholesterol metabolism in man. N Engl J Med 1977;296:1365–1371.

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47. Mok HYI, von Bergmann K, Grundy SM. Regulation of pool size of bile

acids in man. Gastroenterology 1977;73:684 – 690. 53. Bennion LJ, Grundy SM. Risk factors for development of cholelithiasis in

man. N Engl J Med 1978;299:1161–1167. 57. Mok HYI, von Bergmann K, Grundy SM. Effects of continuous and intermittent feeding on biliary lipid outputs in man: application for measurements of intestinal absorption of cholesterol and bile acids. J Lipid Res 1979;20:389 –398. 58. Zech LA, Grundy SM, Steinberg D, Berman M. A kinetic model for production and metabolism of very low density lipoprotein triglycerides: evidence for a slow production pathway and results for normolipidemic subjects. J Clin Invest 1979;62:1252–1273. 59. Grundy SM, Mok HYI, Zech LA, Steinberg D, Berman M. Transport of very low density of lipoprotein-triglycerides in varying degrees of obesity and hypertriglyceridemia. J Clin Invest 1979;63:1274 –1283. 62. Bilheimer DW, Stone NJ, Grundy SM. Metabolic studies in familial hypercholesterolemia: evidence for a gene-dosage effect in vivo. J Clin Invest 1979; 64:524 –533. 66. Howard BV, Zech L, Davis M, Bennion LJ, Savage PJ, Nagulespuran M, Bilheimer D, Bennett PH, Grundy SM. Studies of very low density lipoproteintriglyceride metabolism in an obese population with low plasma lipids: lack of influence of body weight or plasma insulin. J Lipid Res 1980;21:1032–1041. 71. Mok HYI, von Bergmann K, Grundy SM. Kinetics of the enterohepatic circulation during fasting in man: biliary lipid secretion and gallbladder storage. Gastroenterology 1980;78:1023–1033. 72. Sedaghat A, Grundy SM. Cholesterol crystals and the formation of cholesterol gallstones. N Engl J Med 1980;302:1274 –1277. 74. Grundy SM, Mok HYI, Zech L, Berman M. Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man. J Lipid Res 1981;22:24 –36. 84. Beil U, Grundy SM, Crouse JR, Zech L. Triglyceride and cholesterol metabolism in primary hypertriglycerides. Arteriosclerosis. 1982;2:44 –57. 103. Brunzell JD, Albers JJ, Chait A, Grundy SM, Groszek E, McDonald GB. Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. J Lipid Res 1983;24:147–155. 104. Wolf R, Grundy SM. Influence of weight reduction on plasma lipoproteins in obese patients. Arteriosclerosis 1983;3:160 –169. 107. Wolf RN, Grundy SM. Influence of exchanging carbohydrate for saturated fatty acids on plasma lipids and lipoproteins in man. J Nutr 1983;113:617– 620. 110. Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci 1983;80:4124 – 4128. 113. Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin stimulates receptor-mediated clearance of LDL from plasma in familial hypercholesterolemia heterozygotes. Trans Assoc Am Physicians 1983;96:1–9. 115. Kesaniemi YA, Grundy SM. Influence of gemfibrozil on metabolism of cholesterol and plasma triglycerides in man. J Am Med Assoc 1984;251:2241– 2246. 116. Kesaniemi YA, Grundy SM. Dual defect in metabolism of very low density lipoprotein triglycerides in patients with type 5 hyper-lipoproteinemia. JAMA 1984;251:2542–2547. 119. Grundy SM, Bilheimer DW. Infuence of inhibition of 3-hydroxy-3methylglutaryl CoA by reductase by mevinolin in familial hypercholesterolemia heterozygotes: effects of cholesterol balance. Proc Natl Acad Scin (USA) 1984;81: 2538 –2542. 126. Bilheimer DW, Goldstein JD, Grundy SM, Starzl TE, Brown MS. Liver transplantation to provide low-density lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. N Engl J Med 1984;311:1658 –1664. 129. Vega GL, Beltz W, Grundy SM. Low density lipoprotein metabolism in hypertriglyceridemic and normolipidemic patients with coronary heart disease. J Lipid Res 1985;26:115–126. 130. Mattson FH, Grundy SM. Comparison of effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on plasma lipids and lipoproteins in man. J Lipid Res 1985;26:194 –202. 132. Dunn FL, Grundy SM, Bilheimer DW, Havel RJ, Raskin P. Impaired catabolism of very low-density lipoprotein-triglyceride in a family with primary hypertriglyceridenia. Metabolism 1985;34:316 –324. 133. Beltz WF, Kesaniemi YA, Howard BV, Grundy SM. Development of an integrated model for analysis of the kinetics of apolipoprotein B in plasma lipoproteins VLDL, IDL, and LDL. J Clin Invest 1985;76:575–585. 134. Kesaniemi YA, Beltz WF, Grundy SM. Comparisons of metabolism of apolipoprotein B in normal subjects, obese patients, and patients with coronary heart disease. J Clin Invest 1985;76:586 –595. 135. Egusa G, Beltz WF, Grundy SM, Howard BV. Influence of obesity on the metabolism of apolipoprotein B in man. J Clin Invest 1986;76:596 – 603. 136. Vega GL, Grundy SM. Gemfibrozil therapy in primary hyper-triglyceridemia associated with coronary heart disease. JAMA 1985;253:2398 –2403. 141. Grundy SM, Vega GL, Bilheimer DW. Influence of combined therapy with mevinolin and interruption of bile acid reabsorption on low-density lipoproteins in heterozygous familial hypercholesterolemia. Ann Int Med 1985;103:339 –343. 142. Grundy SM, Vega GL, Bilhemier DW. Kinetic mechanisms determining variability in low-density lipoprotein levels and their rise with age. Arteriosclerosis 1985;5:623– 630. 143. Grundy SM, Vega GL. Influence of mevinolin on metabolism of low-density

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lipoproteins in primary moderate hypercholesterolemia. J Lipid Res 1985;26: 1464 –1475. 154. Vega GL, Grundy SM. In vivo evidence for reduced binding of low-density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest 1986;78:1410 –1414. 155. Grundy SM, Nix D, Whelan MF, Franklin L. Comparison of three cholesterol lowering diets in normolipidemic men. JAMA 1986;256:2351–2355. 159. Vega GL, Grundy SM. Treatment of primary moderate hypercholesterolemia with lovastatin (mevinolin) and colestipol. JAMA 1987;257:33–38. 166. Innerarity TL, Weisgraber KH, Arnold KS, Mahley RW, Krauss RM, Vega GL, Grundy SM. Familial defective apolipoprotein B-100: low-density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci (USA) 1987;84:6919 – 6923. 171. Garg A, Grundy SM. Lovastatin for lowering cholesterol levels in noninsulin dependent diabetes mellitus. N Engl J Med 1988;318:81– 86. 172. East C, Bilheimer DW, Grundy SM. Combination drug therapy for treatment of familial combined hyperlipidemia. Ann Intern Med 1988;109:25–32. 173. Grundy SM, Vega GL. Plasma cholesterol responsiveness to saturated fatty acids. Ann J Clin Nutr 1988;47:833– 824. 177. Grundy SM, Florentin L, Nix D, Whelan MF. Comparison of monounsaturated fatty acids and carbohydrates for reducing raised levels of plasma cholesterol in man. Am J Clin Nutr 1988;47:965–969. 178. Bonanome A, Grundy SM. Effect of dietary stearic acid on plasma cholesterol and lipoprotein levels. N Engl J Med 1988;318:1244 –1248. 179. Grundy SM, HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med 1988;319:24 –33. 180. Garg A, Bonanome A, Grundy SM, Zhange Z-J, Unger RH. Comparison of a high monounsaturated fat diet in patients with non-insulin dependent diabetes mellitus. N Engl J Med 1988;319:829 – 834. 181. Uauy R, Vega GL, Grundy SM, Bilheimer DM. Lovastatin therapy in receptor-negative homozygous familial hypercholesterolemia: lack of effect on low-density lipoprotein concentrations or turnover. J Pediatr 1988;113:387–392. 183. Weisgraber KH, Innerarity TL, Newhouse YM, Young SG, Arnold KS, Krauss RM, Vega GL, Grundy SM, Mahley RM. Familial defective apolipoprotein B-100: enhanced binding of monoclonal antibody MB 47 to abnormal low-density lipoproteins. Proc Natl Acad Sci USA 1988;85:9758 –9762. 186. Soria LF, Ludwig EH, Clarke HRG, Vega GL, Grundy SM, McCarthy BJ. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 1989;86:587–591. 191. Vega GL, Grundy SM. Comparison of lovastatin and gemfibrozil in normolipidemic patients with hypoalphalipoproteinemia. JAMA 1989;262:3148 –3153. 193. Garg A, Grundy SM. High monosaturated fat diet for non-insulin-dependent diabetes mellitus. N Engl J Med 1989;320:536 –537. 196. Grundy SM, Vega GL. Causes of high blood cholesterol. Circulation 1990;81:412– 427. 198. Abbott WGH, Swinburn B, Ruotolo G, Hara H, Patti L, Harper I, Grundy SM, Howard BV. Effect of a high-carbohydrate, low-saturated fat-diet on apolipoprotein B and triglyceride metabolism in Pima Indians. J Clin Invest 1990; 86:642– 650. 203. Beltz WF, Kesaniemi YA, Miller NH, Fisher WR, Grundy SM, Zech LA. Studies on the metabolism of apolipoprotein B in hypertriglyceridemic subjects using simultaneous administration of tritiated luecine and radioiodinated very low-density lipoprotein. J Lipid Res 1990;31:361–374. 205. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in noninsulin-dependent diabetes mellitus. JAMA 1990;264:723–726. 209. Vega GL, Grundy SM. Primary hypertriglyceridemia with borderline high cholesterol and elevated apolipoprotein B concentrations. JAMA 1990;264:2759 – 2763. 216. Vega GL, Hobbs HH, Grundy SM. Low-density lipoprotein kinetics in a family having defective low-density lipoprotein receptors in which hypercholesterolemia is suppressed. Arterioscler Thromb 1991;11:578 –585. 220. Grundy SM. Multifactorial etiology of hypercholesterolemia. Implications for prevention of coronary heart disease. Arterioscler Thromb 1991;11:1619 – 1635. 222. Denke MA, Grundy SM. Effects of fats high in stearic acid on lipid and lipoprotein concentrations in men. Am J Clin Nutr 1991;54:1036 –1040. 226. Garg A, Grundy SM, Unger RH. Comparison of effects of high and low-carbohydrate diets on plasma lipoproteins and insulin sensitivity in patients with mild NIDDM. Diabetes 1992;41:1278 –1285. 227. Wilson MA, Vega GL, Gylling H, Grundy SM. Persistence of abnormalities in metabolism of apolipoproteins B-100 and A-1 after weight reduction in patients with primary hypertriglyceridemia. Arterioscler Thromb 1992;12:976 – 984. 229. Gylling H, Vega GL, Grundy SM. Physiologic mechanisms for reduced apolipoprotein AI concentrations associated with low levels of high-density lipoprotein cholesterol in patients with normal plasma lipids. J Lipid Res 1992; 33:1527–1539.

231. Denke MA, Grundy SM. Comparison of effects of lauric acid and palmitic

acid on plasma lipids and lipoproteins. Am J Clin Nutr 1992;56:895– 898. 233. Jialal I, Grundy SM. Effect of dietary supplementation with alpha-toco-

pherol on the oxidative modification of low-density lipoprotein. J Lipid Res 1992;33:899 –906. 235. Vega GL, Grundy SM. Two patterns of LDL metabolism in normotriglyceridemic patients with hypoalphalipoproteinemia. Arterioscler Thromb 1993;13: 579 –589. 237. Gianturco SH, Bradley WA, Nozaki S, Vega GL, Grundy SM. Effects of lovastatin on the levels, structure, and atherogenicity of VLDL in patients with moderate hypertriglyceridemia. Arteriocler Thromb 1993;13:472– 481. 238. Blades B, Vega GL, Grundy SM. Activities of lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol. Arterioscler Thromb 1993;13:1227–1235. 242. Jialal I, Grundy SM. Effect of combined supplementation with a-tocopherol, ascorbate, and beta-carotene on low-density lipoprotein oxidation. Circulation 1993;88:2780 –2786. 243. Arca M, Vega GL, Grundy SM. Hypercholesterolemia in postmenopausal women: metabolic defects and response to low-dose lovastatin. JAMA 1994;271: 453– 459. 250. Abate N, Bruns D, Peshock R, Garg A, Grundy SM. Estimation of adipose tissue mass by magnetic resonance imaging: validation against dissection in human cadavers. J Lipid Res 1994;35:1490 –1496. 254. Cohen JC, Wang Z, Grundy SM, Stoesz MR, Guerra R. Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation of plasma HDL cholesterol levels. J Clin Invest 1994;94: 2377–2384. 256. Abate N, Garg A, Peshock RM, Stray-Gunderson J, Grundy SM. Relationship of generalized and regional adiposity to insulin sensitivity in man. J Clin Invest 1995;96:88 –98. 257. Mize C, Uauy R, Kramer R, Benser M, Allen S, Grundy SM. Lipoproteincholesterol responses in healthy infants fed defined diets from ages 1 to 12 months: comparison of diets predominant in oleic acid versus lenoleic acid, with parallel observations in infants fed a human milk-based diet. J Lipid Res 1995; 36:1178 –1187. 258. Tato F, Vega GL, Grundy SM. Relation between cholesterol ester transfer protein activities and lipoprotein cholesterol in patients with hypercholesterolemia and combined hyperlipidemia. Arterioscler Thromb Vasc Biol 1995;15:112– 120. 259. Tato F, Vega GL, Grundy SM. Bimodal distribution of cholesterol ester transfer protein activities in normotriglyceridemic men with low HDL cholesterol concentrations. Arteriscler Thromb Vasc Biol 1995;15:446 – 451. 269. Vega GL, Grundy SM. Hypercholesterolemia with cholesterol-enriched LDL and normal levels of LDL-apolipoprotein B. Effects of the step I diet and bile acid sequestrants on the cholesterol content of LDL. Arterioscler Thromb Vasc Biol 1996;16:517–522. 272. Abate N, Garg A, Peshock RM, Stray-Gunderson J, Adams-Huet B, Grundy SM. Relationship of generalized and regional adiposity to insulin sensitivity in men with NIDDM. Diabetes 1996;45:1684 –1693. 274. Abate N, Garg A, Coleman R, Grundy SM, Peshock RM. Prediction of total subcutaneous abdominal, intraperitoneal, and retroperitoneal adipose tissue masses in men by a single axial magnetic resonance imaging slice. Am J Clin Nutr 1997;65:403– 408. 276. Tato F, Vega GL, Grundy SM. Determinants of plasma HDL-cholesterol in hypertriglyceridemic patients: role of cholesterol-ester transfer protein and licithin cholesterol acyl transferase. Arteriscler Thromb Vasc Biol 1997;17:56 – 63. 279. Guerra R, Wang J, Grundy SM, Cohen JC. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol. Proc Natl Acad Sci USA 1997;94:4532– 4537. 284. Tato F, Vega GL, Grundy SM. Effects of crystalline nicotinic acid-induced hepatic dysfunction on serum low-density lipoprotein cholesterol and lecithin cholesterol acyl transferase. Am J Cardiol 1998. 285. Vega GL, Clark LT, Tang A, Marcovina S, Grundy SM, Cohen JC. Hepatic lipase activity is lower in African American than in white American men: effects of 5’ flanking polymorphism in the hepatic lipase gene. J Lipid Res 1998;39: 228 –232. 286. Nie L, Wang J, Clark LT, Tang A, Vega GL, Grundy SM, Cohen JC. Body mass index and hepatic lipase gene (LIPC) polymorphism jointly influence post heparin plasma hepatic lipase activity. J Lipid Res 1998;39:1– 4. 287. Wang J, Freeman DJ, Grundy SM, Levine DM, Guerra R, Cohen JC. Linkage between cholesterol 7a-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. J Clin Invest 1998;101:1283–1291. 288. Mostaza JM, Vega GL, Snell P, Grundy SM. Abnormal metabolism of free fatty acids in hypertriglyceridemic men: apparent insulin resistance of adipose tissue. J Intern Med 1998;243:265–274.

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