Anthony Cerami Award in Translational Medicine

A Journey in Science: Medical Scientist in Translation

Göran K Hansson

Karolinska Institute, Department of Medicine Solna and Center for Molecular Medicine at Karolinska University Hospital, Stockholm, Sweden

Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Mo- lecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these his- tories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed and treated. In this volume, the Cerami Award Monograph is by Göran K Hansson, MD, PhD, Karolinska Institute. A visionary in the field of cardiovascular re- search, this is the story of Dr. Hansson’s scientific journey. Online address: http://www.molmed.org doi: 10.2119/molmed.2014.00092

INTRODUCTION I grew up in a small town in the prov- world politics and student protests. The My decision to go to medical school ince of Bohuslän on the Swedish North 1960s were an exciting time. was based in equal parts on a desire to Sea coast. My dad ran the local newspa- help people, a wish to have a meaning- per of the town, and my mum was a MEDICAL SCHOOL AND HOW TO ful job and the challenge to get into a nurse at its small hospital. The town of SURVIVE IT program that was, at the time, the most Lysekil was dominated by the sea sur- The curriculum in medical school coveted one in the Swedish university rounding it. Commercial fishing, her- started with anatomy. It was a night- system. I had dreams of becoming a ring canneries, and a factory producing mare. We were expected to memorize thoughtful psychiatrist, a decisive cardi- boat engines were its main activities. In Latin names for hundreds of structures ologist or perhaps a doctor for the poor summer, the coast was invaded by on bones—fossae, sulci, capita and so on. somewhere in a developing country. tourists from the big cities—Stockholm, We were incessantly told that knowledge I made it to and through medical school, Göteborg and Oslo. When the sea of all these anatomical details was ab- but I fulfilled none of these dreams. warmed up, we went swimming, canoe- solutely necessary for any clinical doctor. After a short time in internal medicine, ing and sailing. Life was magical for a When I started working as a clinician the research bug had bitten me and I be- teenager—sailing in the day and party- myself, I found this kind of descriptive came a physician-scientist, with the em- ing at night. Winds from the big world anatomy completely useless. In real life, phasis gradually moving toward the lat- brought new influences and new bones have tendons and muscles at- ter part of the term. sounds, such as the Beatles, Bob Dylan, tached; they are not bare except in the cemetery. One day, I saw a poster in the corridor outside the anatomy department. The Address correspondence to Göran K Hansson, Karolinska University Hospital, Center for neighboring department of histology in- Molecular Medicine L8:03, SE-17176 Stockholm, Sweden. E-mail: [email protected]; vited students to an evening with infor- Phone: +46-8-5177-6222. mation about medical research. We talked Submitted May 1, 2014; Accepted for publication May 1, 2014; Epub (www.molmed.org) about it over a beer in the park when we September 5, 2014. were skipping another boring hour of anatomy, and decided to attend. That evening, we met other kinds of teachers. They were scientists and told us about

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who had just finished his PhD in Sören’s come and learn. The head of the depart- lab. Göran taught me how to dissect ar- ment was the famous immunologist, teries, analyze in tissues and Örjan Ouchterlony, who had invented the label dividing cells with radioactive iso- immunodiffusion method for analyzing topes. I was learning the craft of science antigens. Much of the work in the depart- (Figure 1). ment still dealt with the “Ouchterlony Life was intense. There were lectures technique,” but they were also doing im- and classes in physiology, pharmacology munofluorescence microscopy. I stained and pathology in the mornings and after- normal rabbit arteries for immunoglobu- noons, work to do in the research lab in lins and complement factors and found the evenings, and books to read at night. nothing. But when I applied the same And there were a thousand things to staining protocol to atherosclerotic arter- protest against in endless demonstra- ies of fat-fed rabbits, there were tons of tions, ranging from the war in Vietnam IgG and C3 in the lesions! Something was to the new curricula in universities. My going on. There was an immune activity girlfriend (and future wife), Margareta, of some kind in the atherosclerotic lesion. who was studying psychology, and I For the first time, I had made a discovery. were busy all the time. And things were to get even busier. POSTDOCTORAL STUDY IN A MECCA Margareta was pregnant, and we hadn’t OF VASCULAR BIOLOGY even finished our educations. Our son, I finished my PhD thesis, applied for a Figure 1. Göran Hansson smashes some Emil, was born the day I had my major postdoctoral fellowship and contacted glassware while trying to isolate organelles. exam in internal medicine. Axel followed scientists at the University of Washington Caricature by student colleague Tom Björnheden, 1980; reproduced with permis- 3 years later. Margareta switched from in Seattle, which was a Mecca for vascu- sion from him. psychology to physiotherapy when it be- lar biology and research. I came obvious that job opportunities was overwhelmed with joy when I was were dwindling in psychology. I contin- awarded a Fogarty International Postdoc- medical problems that needed to be ued in medical school and could even toral Fellowship from the U.S. National solved, pointing out methods for solving continue with part-time research, thanks Institutes of Health and could move to them. And they wanted us to join them in to an understanding wife and a modest Seattle with my little family. that endeavor. We immediately signed up. need for sleep. Seattle was a fun city and the Univer- Our first experiment was not a success. sity of Washington was everything a re- My classmate, Per Elias, and I joined a IMMUNITY IN BLOOD VESSELS? search university should be. I worked neurobiology project to analyze biochem- Immunology immediately captivated with Steve Schwartz, an eccentric, excit- ical changes in the cerebellum after alco- me in medical school. I took immunol- ing and intellectually brilliant scientist in hol exposure. Our main finding was that ogy courses as part of my PhD program the pathology department. Steve’s pas- the cerebellum is completely devoid of and learned about antibodies, vaccina- sion was cell kinetics, and he could argue protein. Neurobiology was not ready for tion and memory. I was fascinated by the for hours about cell cycles and popula- such a paradigm shift, and we decided to fact that this powerful defense system tion dynamics in the endothelium. Next move to other fields. was patrolling our bodies, next to the door was Earl Benditt, the former chair- In the laboratory of Sören Björkerud, I blood vessels where atherosclerosis de- man of the department, who had pro- heard about cardiovascular disease, the veloped. “How would the immune sys- posed that atherosclerosis was a mono- major cause of death in our society. Sören tem react to a pathology that builds up clonal population of smooth muscle cells. was an enthusiastic teacher. It was fasci- in its immediate vicinity?” I asked my- The new chairman, Russell Ross, had an- nating to hear him explain how the cells self. “Someone must know,” I reasoned, other theory—that atherosclerosis was of the blood vessels form a barrier to pre- and I went to the library and read all the caused by the platelet-derived growth vent cholesterol from accumulating and textbooks and review papers I could find factor, which was released when platelets how that barrier could be damaged by about cardiovascular pathology. Not a aggregated at sites of arterial damage. the forces of blood pressure, leading to word was said about the immune sys- Earl and Russell would never reach a atherosclerosis and ultimately to myocar- tem. I asked Göran Bondjers. His answer consensus, but some kind of working re- dial infarction. was “Go and find out.” lationship developed, with Earl being the I was assigned to work with Göran I knocked on the door of the microbiol- king of vascular biology in Seattle and Bondjers, a young physician-scientist ogy department, and they allowed me to Russell in the rest of the world.

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The young generation of cardiovascu- tibodies recognized to characterize the lar scientists was a great crowd. Ron features of the cells forming the lesion. Heimark, a skillful biochemist, patiently I thought I had a better idea and started taught me how to run SDS (sodium do- testing it as soon as I came back to decyl sulfate) gels. Alec Clowes was a Göteborg. promising young vascular surgeon who My idea was to use well-characterized did beautiful work on arterial restenosis, antibodies to known cell types, apply together with his wife Monica, and Alan them to human atherosclerotic lesions Chait, a brilliant endocrinologist study- and find out if they stained any of the ing lipoprotein metabolism. I shared an cells. From the immunology literature, office with an expatriate Brit, Michael I knew about the T- and B-cell–specific Reidy, at the time of the Falklands war antibodies, later to be known by their CD and was offered advice on military strat- numbers, and my friend Giulio Gabbiani egy every day. in Geneva sent us antibodies to smooth Our family had a good time. We made muscle cell components. But where lots of friends, some with whom we still could we find human arteries? Autopsy keep in touch. Weekends were spent material was probably too degraded, so doing excursions into the fantastic nature we needed surgical material. surrounding Seattle, with the Olympic My clinical training helped solve the peninsula, the Cascade Range and the problem. As part of my 21-month intern- Pacific Ocean. In the summer of 1982, we ship at Sahlgrenska University Hospital Figure 2. HLA-DR expression in the human drove down the Pacific coast, camping in in Göteborg, I worked for 4 months in atherosclerotic plaque. HLA-DR protein Oregon and California and having a vascular surgery. I was a lousy surgeon, (green) is expressed by most cells in the wonderful time. I came back to Sweden but I learned a lot and had a good time. atherosclerotic plaque (right side) but not in the normal artery adjacent to it (left in 1983 as a full-fledged cell biologist. I The chief vascular surgeon, Jan Holm, side). This fluorescent micrograph of a sec- knew how to grow endothelial cells and recommended me to use endarterectomy tion from a human endarterectomy sam- material from the carotid artery. Even smooth muscle cells, how to analyze ple led us to propose that atherosclerosis is growth factors and how to assess cell better, Jan offered to provide carotid en- an inflammatory disease driven by a local proliferation. darterectomies for our studies. We struck immune reaction. Reproduced from (42): up a collaboration that lasted throughout Hansson GK; Jonasson L. The discovery of cellular WHERE DO THE CELLS IN THE PLAQUE my years in Göteborg and led to a great immunity in the atherosclerotic plaque. Arte- COME FROM? friendship as well as an exciting scien- rioscler. Thromb. Vasc. Biol. 2009;29(11):1714–7. At this time, the cellular composition of tific endeavor. We were joined by an Also, see (1): the atherosclerotic lesion was still un- MD/PhD student, Lena Jonasson, now Expression of class II transplantation antigen on vas- known. It was a question everyone in the professor of cardiology at Linköping cular smooth muscle cells in human atherosclerosis. field was asking. While most pathologists University. Always enthusiastic, Lena L Jonasson, J Holm, O Skalli, G Gabbiani, G K Hansson thought of it as a smooth muscle lesion, prepared the surgical specimens, cut the Published in Volume 76, Issue 1 histochemical data pointed to a contribu- sections and did the immunostaining. J Clin Invest. 1985; 76(1):125–131 doi:10.1172/JCI111934 tion of macrophages. In the 1950s, John When I came back to the lab in the Poole and Howard Florey in Oxford had evening after a day in the clinic, we identified macrophagelike cells, possibly looked at the results in the fluorescent stained the majority of cells in the plaque emanating from blood monocytes, accu- microscope together. (Figure 2) (1). mulating in the artery wall of fat-fed rab- When looking into the details, we bits. Twenty-five years later, Ross Gerrity INFLAMMATION LEAVES HLA TRACKS found that this antibody recognized in Cleveland described how monocytes The expected suspects were there, but HLA-DR, a major histocompatibility entered the arterial intima of fat-fed we were also in for some surprises. Vas- complex (MHC) protein that presents swine, and Bob Wissler in Chicago de- cular smooth muscle and endothelial antigen to CD4+ T cells. HLA-DR was ex- tected macrophages in lesions of nonhu- cells did not account for more than about pressed not only by macrophages but man primates. Russell Ross was setting half of all cells in the lesions. Suspecting also by a significant proportion of the up a heroic experiment, by using the new that the rest might be macrophages, we smooth muscle cells as well as some en- monoclonal antibody technology to make applied an antibody that was supposed dothelial cells. Therefore, OKIa1 was not antibodies against homogenates of le- to stain macrophages, OKIa1. But the re- a macrophage marker but a marker of sions and then identifying what these an- sults were astonishing. This antibody antigen-presenting capacity. But how did

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HLA-DR end up on smooth muscle cells? logical concepts and proposals of the that all humans would be tolerant to na- We could never detect it in normal arter- paper published in the Journal of Clinical tive low-density lipoprotein (LDL) and ies, only in atherosclerotic plaques. It was Investigation, it was more appealing to the hypothesized that oxidation would break already known that interferon-γ, a proin- cardiovascular community. Our findings tolerance. Therefore, we exposed our flammatory cytokine produced by acti- were soon confirmed by the Ross team T-cell clones to oxidized LDL, in the vated T cells, could induce HLA-DR on and by several other groups. The 1986 presence of antigen-presenting mono- certain target cells. But T cells, the key ac- paper was considered “unpublishable” by cytes. Some of the T cells reacted and tivators and regulators of adaptive im- many of our colleagues, but it has now started to divide; this response was munity, were not supposed to be in- been cited nearly a thousand times. De- blunted when anti–HLA-DR antibodies volved in atherosclerosis. We were, scriptive data are helpful; we need maps were present in the cultures. The inter- therefore, both surprised and excited to orient ourselves in an unknown terrain. pretation was obvious: oxidized LDL when we found that about 10% of all Some key questions that needed to be was taken up by antigen-presenting cells in human plaques were positive for addressed were: what was the specificity monocytes, fragments of LDL protein the T-cell marker OKT3 (recognizing CD3 of the cellular immune response in ather- were bound to HLA-DR and the protein). And when we stimulated osclerosis, and which were the vascular LDL–HLA-DR complex was exposed to smooth muscle cells in culture with inter- effects of the immune effector response? T cells. T cells carrying TCR antigen re- feron-γ, they started to express HLA-DR. How important were the inflammatory ceptors that could bind this complex The time was ripe for proposing a effects of interferon-γ and other cytokines were activated and mounted an immune hypothesis: in atherosclerosis? response. Our paper presenting these findings was published in Proceedings of 1. T cells are recruited to atherosclerotic CHASING IMMUNE SPECIFICITY National Academy of Sciences of the United lesions. To determine the immunologic speci- States of America in 1995 (3). 2. They are activated by an (unknown) ficity of T cells resident in atherosclerotic When we revisited this problem later antigen. lesions, we needed to clone them. This on using the more refined tools of T-cell 3. When activated, these T cells produce step was not a trivial exercise, and we hybridomas, we confirmed that LDL acts the cytokine interferon-γ that activates needed to learn from a master. I had fol- as an autoantigen but also found, to our macrophages and smooth muscle cells. lowed the work of Marc Feldmann in surprise, that T cells recognize native 4. Cytokine-activated cells express im- London on the autoimmune specificity of rather than oxidized LDL epitopes (4). In- mune/inflammatory genes including Graves’ disease and was impressed, both deed, heavy oxidation makes LDL unrec- HLA-DR. by the technology and the biology. ognizable by T cells. Mild oxidation may 5. Inflammation promotes atherosclerosis. Hence, I wrote to Marc and asked if we increase scavenger receptor–mediated We thought this was important enough could visit his lab to learn T-cell cloning. uptake of LDL into antigen-presenting to justify publication in Nature. Unfortu- He kindly invited me and PhD student cells, whereas heavy oxidation destroys nately, the editors of that revered journal Sten Stemme to come to his lab, then at the T-cell epitopes. We proposed that a did not agree with us, and the manuscript the Charing Cross Sunley Research Insti- window of mild oxidation permits both came back by return mail. We had more tute in West London. uptake and recognition and therefore can success with the Journal of Clinical Investi- Sten and I went to London in the win- cause autoimmune reactions to LDL (5). gation, although their reviewers de- ter of 1990 to spend a couple of weeks in manded one control experiment after an- Marc’s lab learning human T-cell cloning. PHYSICIAN OR SCIENTIST? other, delaying the publication for more This was at the time when Marc and his At this stage, it became necessary to re- than a year. They also forced us to tone colleagues made the groundbreaking dis- consider my career plans. I had gone into down our conclusions and hypothesis; covery of the role of tumor necrosis factor medicine with the goal of becoming a cli- therefore, the paper that came out in July in rheumatoid arthritis, which led to a nician, with an aim to practice internal 1985 was not as exciting as the first ver- revolution in rheumatology. We returned medicine or cardiology. Medical research sion of the manuscript (1). to Göteborg, inspired by the spirit at the was a way to get there and to be able to A follow-up paper was written, in Institute and equipped with knowhow on do it better. But with the discovery of the which we provided a map of the cell pop- how to clone T cells. atherosclerosis-associated immune re- ulations in the plaque. It was a straight- Obtaining arterial T cells from patient sponse, I found myself in the midst of an forward, descriptive paper that was samples was not a trivial problem. After extremely exciting research project that published in Arteriosclerosis (now Arte- a year of methodological development, promised to provide new insights into the riosclerosis, Thrombosis, and Vascular Biology Sten had produced enough clones, from pathogenesis of a major lethal disease, [ATVB]) in March 1986 (2). Because the surgical specimens of four patients, to and perhaps even offer new therapeutic paper did not contain the immunopatho- start an antigen challenge. I assumed opportunities. I realized that I did not

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have the capacity to simultaneously lead around in the routine lab disturbing the for immune cytokines and that their re- this line of research, take good care of se- staff.” sponse includes expression molecules verely ill patients and be a good father to Once the decision was made, it was that promote recruitment of immune cells my children. I had to make a choice. easy to move on. Lots of excitement lay to lesions (8–10). Our own work showed, A patient I met as a resident in internal ahead. Equipped with cell culture sys- for the first time, local production of a medicine helped me solve the problem. tems, human tissue specimens and ani- proinflammatory cytokine, interferon-γ, He was 40 years old and had been ad- mal models, and learning the concepts in the atherosclerotic lesion (11). Georg mitted with a major stroke. I saw him and technologies of molecular biology, Wick and Qingbo Xu in Innsbruck identi- when he came to the medicine ward and we were ready to make discoveries. fied heat shock protein-65–reactive T cells found that the stroke had had a disas- in atherosclerotic lesions of hypercholes- trous effect. A computed tomography IMMUNOSUPPRESSANTS, terolemic rabbits (12). Our first review scan showed a large ischemic lesion in INFLAMMATION, AND THE PROBLEM OF papers started to create some interest in the left hemisphere. At this time, no ac- BEING TOO EARLY the topic among cardiovascular scientists tive therapy was available for ischemic Encouraged by Per Peterson, then in (13,14). However, all these findings were stroke. We had nothing to offer this Uppsala and later at Scripps, we tested not sufficient to convince our colleagues young patient with a devastating cere- the effect of an immunosuppressant that any other molecules than cholesterol brovascular condition. drug, cyclosporin A, on arterial injury. and the platelet-derived growth factor We requested that the patient be trans- The effect was striking—postinjury le- were worth investigating. ferred to intensive care and neurorehabil- sions in rat arteries were reduced by At best, cardiovascular conferences itation. But the neurologist found the about 80% (6). I immediately saw the had a session on inflammation on the brain damage too large for meaningful possibility to use immunosuppressants last day of the meeting, when everybody rehabilitation and said “no.” I was upset to prevent restenosis after vascular pro- was leaving town. The two speakers in and tried to argue for my patient, but to cedures. With the new stenting technique the session were usually my friend Peter no avail. The patient’s wife and their two to maintain patency of arteries after in- Libby and I. Peter chaired when I talked young daughters came to visit and left tervention, it might even be possible to about the cellular immunology of athero- crying. The prognosis was poor, and the coat stents with cyclosporin as a slow- sclerotic lesions, and then it was my turn man was likely to remain in need of hos- release preparation to eliminate resteno- to chair while he spoke about cytokine pital care for the rest of his life, with per- sis altogether. signaling in vascular cells. The rest of the sistent paralysis and aphasia. The best Unfortunately, the pharmaceutical in- audience consisted of a few energetic they could hope for was that the man dustry was not as excited as I. At Sandoz postdoctoral scientists who had not yet would die soon. (now Novartis), which produced cy- left the conference. Meeting this patient made me realize closporin, no one wanted to see me. In the mid-1990s, all this changed. the limitations of clinical medicine. As a I got an invitation to Hoffmann-La Vascular biologists, cardiologists and physician, you can do a lot for your Roche, but they all shook their heads, even immunologists were getting inter- patient—but not more than the tools of thinking I was a crazy immunologist ested in vascular immunology and its medicine available at the time allow. As who thought I could cure heart disease role in atherosclerosis. The clinical and a clinician, your hands are tied by the with cyclosporin! We had to give up the epidemiological findings of Atilio Maseri, limitations of medicine. As a physician- project. A few years later, Andrew Marks Mark Pepys and Paul Ridker changed the scientist, you can help stretch those and his colleagues in New York discov- tide. Maseri and Pepys discovered that limitations. ered a similar effect of another immuno- interleukin-6 and its downstream prod- This experience made it easier for me suppressant, rapamycin/sirolimus (7), uct, C-reactive protein (CRP), are ele- to make the decision to focus on science. and were more successful in convincing vated in patients with unstable coronary I switched residency, from internal med- industry. The sirolimus-coated stent is disease (15,16). Ridker, when interrogat- icine and cardiology to laboratory medi- now a multimillion dollar industry. ing large population cohorts, demon- cine. This turned out to be an ideal com- Our hypothesis that atherosclerosis is strated that modest CRP elevations pre- promise. I could focus on research and an inflammatory disease was met with dict future coronary events in healthy development while maintaining con- immense skepticism, although we and middle-aged individuals (17). But CRP tacts with clinical medicine through the others made several findings that sup- does not cause the disease, since pure laboratory service. My eccentric boss, ported this notion. Michael Gimbrone, CRP preparations failed to elicit any Professor Sven Lindstedt, put it bluntly: Peter Libby, Jordan Pober and their col- atherogenic effects. Therefore, the lesion “The task of the residents is to do re- leagues in Boston demonstrated, in cell in the artery wall must “leak” inflamma- search and develop new methods that culture systems and transplant models, tory mediators such as IL-6, which in- we can apply in diagnostics. Don’t run that vascular cells are important targets duces CRP when reaching the liver.

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NEW OPPORTUNITIES AT THE human specimens. It has emerged into portantly to our understanding of KAROLINSKA INSTITUTE the BiKE (Biobank of Karolinska En- atheroprotective immunity (27,28). In December 1994, I was appointed to a darterectomy) biobank with tissue, RNA, More than 15 years later and thanks to new chair in cardiovascular research at DNA, sera, disease history and follow- the work in several labs, we have the Karolinska Institute in Stockholm. up, and, I believe, the world’s largest learned a lot about the autoimmune re- I now had a chance to build up a larger global transcriptome database of human sponse to LDL and the atheroprotective research team, set up new technology atherosclerosis (21). Collaboration with effector mechanisms it triggers (Figure 3). and embark on long-term projects. It was heart surgeons, cardiologists and And although we still do not have a vac- a golden opportunity, and I was excited rheumatologists has also helped us trans- cine or an immunotherapy on the mar- to start working in Stockholm. For the late findings between experimental mod- ket, we have come a long way toward first 2 years, I worked very hard in Stock- els and human disease. that goal. holm Monday through Friday and spent weekends in our home in Göteborg. Two AN ATHEROPROTECTIVE IMMUNE VASCULAR INFLAMMATION GETS HOT years later, when our youngest son had RESPONSE Two major themes had emerged in our finished gymnasium (“high school,” in Two brilliant young postdoctoral scien- lab: the adaptive immunity of atheroscle- US terms), we sold our apartment in tists, Antonino (Tony) Nicoletti and rosis and the vascular biology of inflam- Göteborg and moved to Stockholm. Al- Giuseppina (Pina) Caligiuri, both now in mation. While a T cell–focused team though Margareta in particular missed Paris, had joined the team and led the studies the autoimmune properties of Göteborg, Stockholm is a great city that work on immunomodulation. Tony and I LDL, the mechanisms of its presentation we enjoy living in, a beauty on the water, were thrilled when we saw that intra- as antigen and the effects of immuniza- with a rich history and a great cultural venous immunoglobulin treatment inhib- tion on disease, a second team in the lab life. ited disease progression (22). This and a works on the vascular biology of im- I decided to set up two new technolo- parallel study by Francois Mach and mune inflammation. gies. The first one was obvious: to estab- Peter Libby showing a similar effect The second line of work got a kick- lish a genetic mouse model for atheroscle- when blocking the immune costimula- start when Yong-jian Geng joined us as rosis. Because all possible immunological tory factor CD40L (23) were the first stud- a PhD student in 1990. His cDNA reagents were available and many mole- ies to demonstrate a therapeutic effect of cloning of rat iNOS (NOS2) (29,30) cules and genes were identified in the immunotherapy on atherosclerosis. brought us into the core of molecular bi- mouse, I was convinced that such a Pina performed another exciting ex- ology technology, and I learned that a model would make it possible to dissect periment. She splenectomized mice with research project is an excellent way of the immunopathogenesis of atherosclero- the thought that removal of a major im- establishing a new technique. When sis to an extent that was unthinkable mune organ might affect atherosclerosis. Yong-jian moved to the United States, when using other species such as rabbits The effect was remarkable—lesions of Zhong-qun Yan continued the vascular or rats. A golden era for experimental ath- splenectomized apoe–/– mice were twice biology research and expanded into in- erosclerosis dawned when Nobuyo as large as those in intact apoe–/– controls nate immunity (31,32). Zhong-qun Maeda and Jan Breslow knocked out the (24). By transfer experiments, we could moved with me to Stockholm, and we apoe gene in mice, and the Dallas team of show protective effects of T cells, but continue to collaborate, 20 years later. Mike Brown, Joe Goldstein and Joachim even more so of B cells. The immune re- At the Karolinska Institute, Guro Valen Herz made an ldlr–/– mouse (18–20). We sponse apparently contained an athero- joined us as a postdoctoral fellow, set up an apoe–/– colony at the Karolinska protective component that resides with a learned vascular biology and taught us Institute, characterized its cellular pathol- population of B cells in the spleen. heart physiology (33). After her postdoc, ogy and went on to test the effect of im- While I was busy setting up my new she set up her own lab in the physiol- munomodulation on atherosclerosis. lab in Stockholm, the labs of Joe Witztum ogy department and later moved to My second initiative was to team up and Jan Nilsson published some very ex- Oslo to take up a professorship in phys- with the clinicians. In Göteborg, I had citing findings. They reported that im- iology. Another postdoctoral scientist, had fruitful collaborations with the vas- munization of fat-fed rabbits with oxi- Gabrielle Paulsson-Berne (34), is now cular surgeons, and it was natural for me dized LDL reduced rather than increased our lab manager as well as an expert in to establish a similar relationship with atherosclerosis (25,26). Our spleen cell molecular biology. A gifted physician- Jesper Swedenborg, Ulf Hedin and their findings identified a mechanism for this scientist, Magnus Bäck, introduced us to colleagues at Karolinska Hospital. We set protection (24), and I set up the goal to eicosanoid biology and leukotriene sig- up a pipeline between the cardiovascular develop a vaccine against atherosclerosis. naling (35). He now runs his own re- surgery theater and our lab in the Center Later on, the discovery that regulatory search program on vascular inflamma- for Molecular Medicine to obtain fresh T cells inhibit atherosclerosis added im- tion at our center, while also serving as

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mune response to LDL accumulation in the artery wall.

NEW OPPORTUNITIES AND NEW EXCITEMENT At the moment, we have an exciting set of scientific questions, a great panel of techniques to address them and a superb team to solve the problems. We have been able to translate many of our find- ings to human pathology and some to clinical development. With the exception of the coated stents, vascular immunol- ogy has not reached clinical therapy, but we remain hopeful that it will do so in the years to come. Ongoing clinical trials on interleukin-1β blockade and methotrexate-based immunosuppression should be informative, as should clinical studies of vaccination. Translational med- icine is a slow but exciting process! To be a medical scientist is stimulat- ing not only because of the intellectual challenges you are facing, but also be- cause of the discoveries you may make. Our workplace is global; we address similar problems and methods wherever we are located and we can easily cross borders created by language, culture or politics. Our apprentice system called the postdoctoral fellowship creates unique opportunities to live in another country and get to know another cul- Figure 3. Counterbalancing forces of adaptive immunity in the atherosclerotic plaque: ture. I get a kick every morning when I proinflammatory Th1 cells and atheroprotective Treg cells, as proposed in a review article come to work and meet my colleagues (43). We have since learned that native rather than oxidized LDL serves as a T-cell anti- from Asia, Europe and the Americas gen. Reproduced from (43): (Figure 4). Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 2005;352(16): The position at the interface between 1685–95. Copyright © 2005 Massachusetts Medical Society. Reprinted with permission. basic life science and clinical medicine is very special. You learn from both sides a consultant in cardiology at Karolinska crossbreeding and transplantation tech- and appreciate all the various kinds of University Hospital. niques. Their work identified immune expertise that are needed for a transla- Our studies of adaptive immunity responses that promote vascular inflam- tional research project, from biochem- were facilitated immensely by the avail- mation and atherosclerosis, but also istry to surgery. I have had the privilege ability of gene-targeted mouse models. other responses that inhibit lesion de- of working together with a series of out- A succession of fellows including velopment, modulate lipoprotein metab- standing basic and clinical scientists at Xingha Zhou, Anna-Karin Robertson, olism and cause plaque stabilization the Karolinska’s Center for Molecular Ariane Sultan, Daniel Johansson, (4,28,36–39). Medicine. My lab neighbors include the Roland Klingenberg, Norbert Gerdes, After decades of controversy, it is time surgeon and cell biologist Ulf Hedin, the Andreas Hermansson, Daniel Ketelhuth, to reconcile the views of atherosclerosis cardiologist/geneticist Anders Hamsten, Anna Lundberg, Olga Ovchinnikova, as a metabolic disturbance or a response the rheumatologists/immunologists Daniela Strodthoff, Anton Gisterå and to injury. Atherosclerosis is a chronic in- Lars Klareskog and Marie Wahren- others addressed these aspects, by using flammatory disease caused by an im- Herlenius, the neurologist/immunologist

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Figure 4. Hansson Lab 2014. Upper row: Anton Gisterå, Zhong-qun Yan, Daniel Ketelhuth, Andres Laguna Fernandez, Reiner Mailer, Roland Baumgartner, André Strodthoff, Marcelo Petri, Stephen Malin, Martin Berg. Middle row: John Pirault, Olga Ovchinnikova, Miguel Cao- racedo, Sophie Xintong Jiang, Monica Centa, Linda Haglund, Katrin Habir, Gabrielle Paulsson-Berne, Konstantinos Polyzos. Lower row: Glykeria Karadimou, Maria Klement, Teodora Andonova, Göran Hansson, Ann Hellström, Anneli Olsson.

Tomas Olsson and the virologist Cecilia into many aspects of science. I have had with me since then, as an island of es- Söderberg-Nauclér, to mention a few. Our the very special privilege of serving on cape and a sheer pleasure. It remains a research network Center of Excellence the Nobel Committee for Physiology or challenge to be a reasonably complete for Research on Inflammation and Car- Medicine for 15 years (41). By forcing human being, but you must never stop diovascular disease (CERIC) gives all of me to learn about many different areas trying. us access to unique biobanks and animal of life science and medicine, my work models of several inflammatory diseases, with the Nobel Prize is a continuing sci- ACKNOWLEDGMENTS including atherosclerosis, multiple scle- entific education and a wonderful I am grateful to all present and former rosis and rheumatoid arthritis (40). Our source of excitement and intellectual fellows and students in our lab for mak- biochemistry partners Jesper Haeggström, stimulation. ing it such a great place to work. I am Thomas Renné and Rikard Holmdahl Science is a very large part of life for also indebted to many colleagues for add expertise in fundamental sciences to any scientist, and particularly so in trans- stimulating discussions and collabora- our network. With support from the lational medicine, since you try to bridge tion, in the Center for Molecular Medi- Linnaeus program of the Swedish Re- between two very dynamic areas: molec- cine at Karolinska Institute and all over search Council, our vision for a transla- ular life science and clinical medicine. It the world. I gratefully acknowledge the tional research center in inflammation is, nevertheless, important to find time support of the funding agencies that and cardiovascular disease has finally for other activities. Family life has al- made our research possible. Our work is become a reality. ways been a source of joy for me, as has currently supported by the Swedish Re- Scientific journals, conferences and music. I was introduced to classical search Council, the Swedish Heart-Lung organizations provide opportunities to music as an aspiring pianist with limited Foundation, the European Commission extend our networks and to get insights talent in my teens, and it has remained and the Foundation for Strategic Re-

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search. Finally, I thank my wife Mar- 13. Hansson GK, Jonasson L, Seifert PS, Stemme S. 29. Geng YJ, Almqvist M, Hansson GK. (1994) cDNA gareta and our sons Emil and Axel for a (1989) Immune mechanisms in atherosclerosis. cloning and expression of inducible nitric oxide wonderful life together. Arteriosclerosis. 9:567–78. synthase from rat vascular smooth muscle cells. 14. Libby P, Hansson GK. (1991) Involvement of the Biochim. Biophys. Acta. 1218:421–4. immune system in human atherogenesis: current 30. Geng YJ, Hansson GK, Holme E. (1992) Inter- DISCLOSURE knowledge and unanswered questions. Lab. In- feron-γ and tumor necrosis factor synergize to in- I have no competing interests as de- vest. 64:5–15. duce nitric oxide production and inhibit mito- fined by Molecular Medicine, or other in- 15. Liuzzo G, et al. (1994) The prognostic value of chondrial respiration in vascular smooth muscle terests that might be perceived to influ- C-reactive protein and serum amyloid a protein in cells. Circ. Res. 71:1268–76. severe unstable angina. N. Engl. J. Med. 331:417–24. 31. Yan Z, Hansson GK. (1998) Overexpression of in- ence the results and discussion reported 16. Liuzzo G, et al. (1996) Plasma protein acute- ducible nitric oxide synthase by neointimal in this paper. phase response in unstable angina is not induced smooth muscle cells. Circ. Res. 82:21–9. by ischemic injury. Circulation. 94:2373–80. 32. Edfeldt K, Swedenborg J, Hansson GK, Yan ZQ. REFERENCES 17. Ridker PM, Hennekens CH, Buring JE, Rifai N. (2002) Expression of toll-like receptors in human 1. Jonasson L, Holm J, Skalli O, Gabbiani G, Hans- (2000) C-reactive protein and other markers of atherosclerotic lesions: a possible pathway for son GK. (1985) Expression of class II transplanta- inflammation in the prediction of cardiovascular plaque activation. Circulation. 105:1158–61. tion antigen on vascular smooth muscle cells in disease in women. N. Engl. J. Med. 342:836–43. 33. Valen G, Yan ZQ, Hansson GK. 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