Stephen G. Young

Abstract

HomeCirculation ResearchVol. 123, No. 11Stephen G. Young Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBStephen G. YoungA “History Major” Finds a Career in Basic Biomedical Research Tamer Sallam Tamer SallamTamer Sallam Search for more papers by this author Originally published8 Nov 2018https://doi.org/10.1161/CIRCRESAHA.118.314236Circulation Research. 2018;123:1192–1195Stephen G. Young grew up in Kansas and studied the history of science at Princeton University. After medical school at Washington University in St Louis, internal medicine training at the University of California, San Francisco (UCSF), and cardiology training at the University of California, San Diego (UCSD), he joined the laboratory of Joseph Witztum at UCSD. Thanks to Witztum and fortuitous interactions with other teachers, Young’s career slowly evolved from clinical cardiology to basic research. After a 17-year stint at a UCSF-affiliated research institute, Young moved to the departments of medicine and human genetics at the University of California, Los Angeles (UCLA). There, he and 2 faculty colleagues, Loren Fong and Anne Beigneux, identified an endothelial cell protein, GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1), that is required for the lipolytic processing of triglyceride-rich lipoproteins. They showed that GPIHBP1 binds LPL (lipoprotein lipase) in the interstitial spaces and shuttles it across endothelial cells to its site of action in the capillary lumen. In the absence of GPIHBP1, LPL remains stranded in the interstitial spaces, resulting in impaired triglyceride processing and severe hypertriglyceridemia. Young and Fong have also studied the role of the nuclear lamins in health and disease. They defined the in vivo functional relevance of lamin B1 and lamin B2, demonstrating that both proteins are required for neuronal migration in the developing brain. They have also been leaders in investigating treatment strategies for diseases caused by genetic defects in prelamin A. Young has received multiple honors and is a member of the National Academy of Sciences (1 of 5 members who are board-certified cardiologists).Download figureDownload PowerPointCan You Tell Us About Your Upbringing?I grew up in Topeka, Kansas, the son of a high-school teacher and an associate dean at a municipal university (Washburn University). My parents were products of the great depression, and they valued education. While I could not claim to have taken full advantage of the educational opportunities in Topeka, I was the top student in my high school class and had terrific choices for my college education.I decided on Princeton University, where I majored in history. I was inspired by my college advisor, Thomas Kuhn (a historian and philosopher of science, “Structure of Scientific Revolutions”); James McPherson (a groundbreaking Civil War historian, “Battle Cry of Freedom”); Charles Gillespie (a historian of science, “Genesis and Geology”); and Carl Hempel (a philosopher of science, “Scientific Explanations”). My college thesis, supervised by Thomas Kuhn, dealt with Charles Dalton and the atomic theory. I seriously considered going to graduate school and becoming a historian, but I ultimately decided on medical school—despite having taken the bare minimum of science classes. My decision was influenced by my older brother Jim, who was about to start medical school at Duke.In retrospect, studying history the of science was a good decision. The courses were exciting, and they gave me some practice in writing. Persuasive writing is one of the keys to being a scientist.I applied to only one medical school, Washington University in St. Louis, in order to be close to my mother, who was ill with metastatic breast cancer.At What Point Did You Find the Scientific Side of Medicine?As a medical student, I had never once envisioned a career in research. In hindsight, however, there were some clues that foreshadowed my shift to a career in science. One was that I enjoyed learning from scientists. In my preclinical years, I was thrilled to learn lipid biochemistry from Roy Vagelos. As a third-year student, my favorite professors were Stuart Kornfield and Philip Majerus. I was vaguely aware that Kornfeld and Majerus were scientists, but as far as I was concerned, they were simply my favorite clinicians. I also have great memories of Michael Brown and Joseph Goldstein visiting Washington University to give a lecture on the LDL receptor and familial hypercholesterolemia (≈1977 or 1978). Even then, long before their Nobel prize, they were scientific celebrities and the entire medical school was buzzing with excitement. Their lecture was extremely inspirational, but my plans to be a clinician were so firmly entrenched that their presentation did not lead me to consider a research career for myself.As a fourth-year medical student, the chairman of the department of medicine, David Kipnis, called me to his office and strongly encouraged me to stay at Washington University for internal medicine training. I explained to him, repeatedly, that I wanted to work with my brother Jim, who was a medical intern at UCSF. Kipnis simply would not take “no” for an answer, but after about 45 minutes he became frustrated and terminated our meeting, commenting, “you are a very confused young man.” Looking back, Kipnis’s comment was probably on target. During our conversation, I had almost certainly revealed how little thought I had given to my future career in medicine.I moved to UCSF for internal medicine training. As a medical intern at San Francisco General Hospital, my first resident was Stanley Korsmeyer. When Stan mentioned that he was interested in pursuing scientific training, I was utterly surprised. While I was intrigued by Stan’s plans (and probably also a little jealous), I continued to devote my energy to clinical medicine. Instead of exploring research opportunities at UCSF, I spent my spare time moonlighting in local hospitals. I also volunteered as a physician at Grateful Dead concerts. (Those concerts were so much fun, particularly the concerts on New Year’s Eve!)The most important part of my experience at UCSF—and the one that had the greatest impact on my life—was working with a UCSF medical student and future wife, Lorraine Clarke Young, now the clinical chief of dermatology at UCLA. Lorraine’s support has been crucial for my career.I moved from UCSF to UCSD for clinical cardiology training. The fellowship program required a year of research. Nearly all of the laboratory-based cardiology faculty at UCSD were interested in hemodynamics and myocardial function. The leadership within UCSD’s cardiology division encouraged me to work with a young faculty member who used nuclear medicine approaches to image and quantify left ventricular function. I never considered that advice, which was fortunate because the imaging laboratory was soon disbanded. (Had I followed the advice from the cardiology division, my research career would have ended before it started!) Instead, I decided to work with Joseph Witztum, an endocrinologist who studied lipid metabolism. I think that this decision to veer towards metabolism was somehow influenced, at least a subconscious level, by influential teachers like Kuhn, Vagelos, Kornfeld, and Korsmeyer. As an MD who had never even seen a pipette, I was lucky to be offered a position in the Witztum laboratory. I began by characterizing a panel of monoclonal antibodies that we developed (along with Linda Curtiss) against apoB, the major protein component of LDL (low-density lipoproteins). With Joe’s guidance, I characterized an apoB-specific monoclonal antibody that abolishes the binding of LDL to the LDL receptor, obtained immunochemical evidence that apoB48 and apoB100 originate from the same gene, and discovered the first examples of truncated apoB proteins in patients with familial hypobetalipoproteinemia (a genetic syndrome characterized by very low levels of LDL cholesterol).1 Initially, I had no plans to pursue research beyond the one-year requirement, but the promising results kept me plugging away. Joe was supportive and even gave me a desk in his own office. Amazing!After my cardiology fellowship and serving for a year on the UCSD faculty, I was fortunate to find a research position in a UCSF-affiliated research institute on the San Francisco General Hospital campus (Gladstone). I remained there for 17 years. That opportunity was pivotal in my career, simply because it forced me to focus on basic science. I had terrific trainees, including Mac Linton, Bob Farese, Murielle Véniant, Martin Raabe, Ed Kim, Sally McCormick, Lars Bo Nielsen, Martin Bergo, and Anne Beigneux. They mentored me as much as I mentored them. We had a lot of fun and some successes: identifying specific APOB mutations associated with familial hypobetalipoproteinemia; creating transgenic and knockout models to examine the role of apoB in lipoprotein metabolism and atherosclerosis;2 and using genetically modified mice to define the in vivo relevance of enzymes involved in the posttranslational modifications of isoprenylated proteins.The extraordinary resources of the San Francisco General Hospital (SFGH) research institute gave me the opportunity to learn new experimental approaches, for example the techniques for generating knockout and knock-in mice. Also, the research institute employed scientific editors who helped me hone my writing skills. Although I continued to work as a cardiologist at SFGH, the research side of my life gradually prevailed. I was never successful in integrating my research and clinical interests in a productive fashion. Moreover, the department of medicine at UCSF shifted its emphasis to outcomes research, and opportunities for laboratory-based physician-scientists became more limited.In 2004, I was recruited to UCLA by the chairman of the department of medicine, Alan Fogelman. He has been very committed to investigator-initiated basic science research in the department of medicine.How Did You Come to the Actual Problem That You Wanted to Study?In the early stages of my career, I was an opportunist. A huge part of being a scientist is recognizing an opportunity and then “jumping on it.” I jumped on APOB mutations affecting plasma cholesterol levels and jumped on using gene targeting to explore lipoprotein metabolism and the enzymes for the posttranslational processing of isoprenylated proteins. The opportunism gradually gave way to digging deeper into scientific stories. A successful career in biomedical research is all about contributing scientific vignettes (both big and small) to a sustained scientific story. Over the past 14 years at UCLA, Loren Fong, Anne Beigneux, and I have worked as a team on two stories, the roles of LPL and GPIHBP1 in plasma triglyceride metabolism and the role of nuclear lamins (which are isoprenylated proteins) in health and disease.You Have Been Involved With Key Discoveries in the Field of Lipid Metabolism Including Identifying GPIHBP1, a Critical Protein Involved in Triglyceride Processing. What Was the Moment of Discovery Like?In large part, I credit our discovery of GPIHBP1 to my medical education. In his biochemistry lectures, Roy Vagelos pointed out that LPL is made by adipocytes and myocytes, but that its site of action is in the capillary lumen. The mechanism by which LPL managed to reach the capillary lumen was a puzzle. Decades later, when Loren, Anne, and I learned that a deficiency in a GPI-anchored protein (GPIHBP1) caused severe hypertriglyceridemia, we recognized that we might be on the verge of a discovery. Along with talented trainees (Michael Weinstein, Conni Voss, Brandon Davies), we proved that GPIHBP1 is produced by capillary endothelial cells and that its main function is to capture LPL in the subendothelial spaces and transport it to the capillary lumen.3–5 Ongoing collaborations with Michael Ploug, a Danish protein chemist, have been extremely helpful in defining LPL–GPIHBP1 interactions. During the past two years, we have extended our studies on triglyceride metabolism (along with Haibo Jiang, Cuiwen He, and Xuchen Hu) to visualize the fatty acid products of triglyceride hydrolysis as they move across capillary endothelial cells and enter surrounding parenchymal cells.6My interest in clinical medicine also contributed to our other research focus‚ the role of nuclear lamins in health and disease. As a medical student, I read every page of the Beeson and McDermott textbook of medicine. Early on in the textbook, there was a paragraph on progeria, a precocious aging syndrome. I was fascinated that such a disorder existed! Decades later, while investigating the enzymatic processing of isoprenylated proteins, Loren and I learned of a link between our biochemical studies and a progeroid disorder caused by a defect in an isoprenylated nuclear lamin protein (prelamin A). Along with talented trainees (Catherine Coffinier, Hea-Jin Jung, Shao Yang, Paul Kim, Natalie Chen), we pursued that link and began to study nuclear lamins intensively.7,8How Did You Manage to Balance Your Role as a Physician and as a Scientist?Early in my career, I was devoted to both clinical cardiology and basic research. Eventually, however, the demands of my research program limited my ability to pursue my clinical interests. As a consequence, I stopped attending on the cardiology service.In recent years, when I have interviewed applicants for UCLA’s MD/PhD program or the cardiology fellowship program, the majority of applicants specify a percentage of time that they intend to dedicate to research. Such plans are pointless. The careers of virtually all physician-scientists evolve, and they generally end up focusing on a single endeavor—clinical medicine, teaching, administration, or research. In my case, I would have been happy to be a practicing physician, but my career gradually veered towards basic science.I would offer one piece of advice about striking a balance between clinical and research activities: Because careers almost always evolve and end up focusing on a single endeavor, persistent efforts to straddle the fence may not be worth the effort. After age 50 or 55, there are some physicians who remain at the pinnacle of basic research and clinical medicine, but in my opinion, they are extremely rare. Physicians should follow their interests and accept the reality that careers evolve. If you enjoy basic science, it is reasonable to stop straddling the fence and leave the clinic behind.What is Special About the Research Environment at UCLA?For me, the most enjoyable part of UCLA has been working with Loren Fong, Anne Beigneux, and our trainees. We have been an effective team, and teamwork is essential for survival at UCLA. Plus, I have been extremely grateful for the support from Alan Fogelman and UCLA’s department of medicine.What Advice Would You Offer Aspiring Physician-Scientists Today?1. Keep an open mind about diverse career possibilities. Shutting out consideration of certain career possibilities can be quite comforting on a psychological level, but it is important to remain open to many possibilities. If you find yourself inspired by a scientific topic, take the time to ask yourself why—and then read, investigate, explore, and solicit advice. And if you find yourself inspired by a speaker, then ask yourself why. Be curious about the possibilities—even if pursuing the possibilities might mean packing up and moving to a different city. When I was a medical student, I dismissed, with little or no thought, a huge range of career possibilities—including careers in biomedical science. Shutting out possibilities likely allayed s my anxieties, but it was a mistake.After committing to a career direction, curiosity and maintaining an open mind are equally important. Scientific progress depends on letting your guard down and taking the time to explore new hypotheses and new experimental approaches.2. You needn’t have completed a MD/PhD program to consider a career in basic biomedical research. Interest in biomedical research can awaken at different times. In my case, the spark occurred after completing training in internal medicine and cardiology. A late awakening is not uncommon, and it is not a problem! One need not have gone through an M.D./Ph.D. program. If you are curious and interested, then you will very quickly make a positive impact in basic research. I am a fan of UCLA’s STAR (Specialty Training and Advanced Research) program, which allows physicians to obtain rigorous research training while pursing clinical fellowship training. These programs belong in every medical school and should be supported to the same extent as MD/PhD programs.3. For a career in biomedical research, an extraordinary intellect is not required, but integrity is essential. Albert Einstein observed: “Most people say that it is the intellect which makes a great scientist. They are wrong: it is character.” Such insight! Indeed, character is the most important determinant of success in a scientific career. By character, I mean showing up to work, working hard, performing careful experiments, analyzing data rigorously, replicating your results, pursuing a sustained story rather than jumping on the latest bandwagon, treating colleagues with respect, investing in the success of colleagues, giving credit to others, and sharing your insights freely. If you do these things, discoveries are inevitable.4. You can take pride in a basic research career. As a young faculty member in San Francisco, I remember being inspired by reading a 1996 interview of Michael Brown and Joseph Goldstein.9 They were asked about the dangers of medical schools focusing excessively on health care delivery. Joe answered by pointing out how important it had been that basic scientists had learned how to culture the polio virus and how to create a vaccine. Without that effort, he said that health care systems would be figuring out the “best ways to put the largest number of iron lungs in the smallest space for the lowest cost.” Mike added that they would be “figuring out whether you really need oxygen in an iron lung or you could do it just with ordinary air. We’d have all kinds of studies of that.” The lesson that I took away from their comments: basic research is important, rewarding, and absolutely crucial for attacking the public health issues of the 21st century.My perception is that most medical students, interns, and residents generally appreciate the importance of basic research but often do not see a pathway for pursuing science as a career. Often, they suspect that all such possibilities have been foreclosed, or they harbor doubts about their ability to pursue basic research. Unfortunately, there are plenty of medical school faculty who fuel these sorts of worries. The challenge for academic medical centers is to do a better job of highlighting the rewards of basic research careers.5. Be careful about choosing a mentor; this will require work! Those who bring donuts to hospital rounds may not be the best mentors in research laboratories, and recommendations by division chiefs or department chairman can be way out of date and dead wrong. Yes, you should solicit advice, but it is probably more important to investigate for yourself. You need to read publications, think about the importance of the topic, and do your best to consider the quality of the data and the quality of the writing. Read the mentor’s grant proposals. Think about whether the mentor has fresh ideas, whether he/she is truly excited about science and pursues science with integrity.In addition to finding a great mentor, it is increasingly important to find a mentoring environment—either within a center, an institute, or a very cohesive division. Several decades ago, senior faculty members had time to mentor young faculty and assist them with scientific directions, manuscripts, and grants. Now, senior faculty spend increasing amounts of time on their own grants and manuscripts, and there is less time for mentoring young scientists. The odds are stacked against postdoctoral fellows or young faculty members who are isolated—either geographically or intellectually. A supportive center, institute, or cohesive division is very important.6. As a faculty member, you do not need to worry about “training” the next generation of scientists. In his 1988 ASCI (American Society for Clinical Investigation) presidential address,10 Robert Lefkowitz wrote that he associated “training” with dogs or monkeys, and he argued that it is not really possible to train a scientist. He argued that the responsibility for training lies with the trainee and that the role of the mentor is simply to try to be a model scientist, to pursue science with integrity, to be open about the challenges and ethical dilemmas in science, and to communicate the thrill of scientific discovery. I agree.An important corollary is that institutions should not dwell on strategies for training scientists. Efforts by administrators to teach mentoring, laboratory management, or grant writing are generally a waste of time and effort. Instead, institutions simply need to focus on identifying and then investing in faculty who pursue research with integrity and communicate the thrill of discovery.7. Be wary of institutional schemes for curing a disease. These plans are rarely useful, either for careers or for scientific progress. Instead, institutions should focus on creating vibrant scientific neighborhoods and supporting investigator-initiated research. That is the best strategy for making discoveries and curing diseases.8. Think carefully about taking on large administrative tasks. Biomedical science requires a full-time commitment; making discoveries is time-consuming and challenging. Nevertheless, the thrill of making discoveries, even small ones, makes the life of a scientist rewarding. Plus, laboratory research is an extremely social endeavor—more so than clinical medicine. The personal interactions with scientific colleagues and trainees are extremely rewarding.If You Were not a Scientist, What Else Do You Think Would Have Captivated You?In a next lifetime, I probably be a physician-scientist all over again. If not that, then a columnist for the New York Times. If not that, then a Civil War historian (following in the footsteps of James McPherson) or a historian of scientific discovery, like Thomas Kuhn and Charles Gillispie.