Anthony Cerami Award in Translational Medicine

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

Lawrence Steinman

Department of Neurology and Neurological Sciences, Stanford University, Stanford, California

Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. 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 Lawrence Steinman, MD, of Stanford University in California. A visionary in the field of neurology, this is the story of Dr. Steinman’s scientific journey. Online address: http://www.molmed.org doi: 10.2119/molmed.2015.00263

It is claimed that the brain is an polio infection in her brain and spinal cord. paths intersected in my first experience “immune privileged” site and there is a With this stark evidence, although I did with laboratory research. special environment that it inhabits, pro- not comprehend it at the time, there was My research career has taken me tected from immune attack. This doctrine no way that “immune privilege” might repeatedly to the matter of whether is probably no more than a fable. The actually exist for the brain. the brain is immune privileged or not. brain is not immune privileged, as I shall Perhaps there is a real irony My colleagues and I discovered a potent share with you. behind how my career has evolved. therapy for the most common immune My first encounter with the concept Although the brain is not an disease of the brain—multiple ­sclerosis of the brain and its supposed state of immune-privileged site, it has been an (MS). However, the U.S. Food and immune privilege was hardly abstract. honor and a privilege to study the inter- Drug Administration (FDA)-approved On August 15, 1951, at age 3, when return- actions of the brain and the immune therapy for MS has a real vulnerability. ing home from a sweet vacation with my system over nearly half a century. The therapeutic known as natalizumab grandparents in the countryside, I found Three years after my sister, Ruth, (Tysabri), in protecting the brain from an that my sister, Ruth, age 6, had been contracted polio, when the Salk immune attack in MS, allowed the brain stricken with poliomyelitis while at sum- ­vaccine (1) first became available, to ­actually become immune privileged, mer camp. Ruth was hospitalized in the I vividly remember standing in line to thereby permitting a devastating viral Contagious Disease Ward of the Los Angeles­ receive this miraculous gift from the infection to develop. Once again, from County Hospital, battling with all the field of immunology. Jonas Salk became my research, I witnessed firsthand might of her immune system against a a family hero, and a decade later, our another big hole in that fable known as “immune privilege and the brain.” Immune surveillance of the brain does Address correspondence to Lawrence Steinman, Department of Neurology and exist, and impairing this immune func- Neurological Sciences, Stanford University, Stanford, CA 94305. Phone: +650-725-6401; tion resulted in opportunistic infections. Fax: +650-725-0627; E-mail: [email protected]. Here I will share my experiences Submitted December 21, 2015; Accepted for publication December 22, 2015; Published in developing therapies for immune Online (www.molmed.org) June 2, 2016. diseases of the brain. The ultimate aim of this research is to try to successfully implement antigen-specific tolerance for autoimmune diseases in the brain and

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elsewhere, so that we can leave normal at NYU and my mother was at Hunter also shared this propensity to teach immune surveillance intact (2). College (Figure 1). with a touch of humor. Kline wrote, Mathematics fascinated me as “I would urge every teacher to become LIFE IN A PRIVILEGED TIME FOR a child. My father was one of my an actor. His classroom technique must SCIENCE EDUCATION best teachers. Norm Steinman once be enlivened by every device used in One of my favorite high school shared with me a paper from his NYU theatre. He can be and should be dra- mathematics teachers, Patrick Perrone, mathematics professor, Morris Kline. matic where appropriate. He must not known as p2 (P squared), referred to ­Professor Kline encouraged my father only have facts but fire. He can utilize me as “Lucky Larry.” Indeed, I have to continue in mathematics and to even eccentricities of behavior to stir up been very lucky with timing. Born aspire to become a math professor. human interest. He should not be afraid after World War II, the Great Depres- Kline ­himself completed his PhD in of humor and should use it freely. Even sion, and the Holocaust, I grew up in 1936 and had a remarkable career as a an irrelevant joke or story perks up the the sunny sheltered environment of mathematician and educator. class enormously” (3). One of my other middle class America, in Culver City, My father shared Kline’s gift for favorite ­mathematics professors, the California. My parents put a high value teaching mathematics and for teaching beloved Professor Raymond Redheffer, on both education and creativity. My in general. In World War II, my father, a started his calculus class at UCLA in mother, Anne, was remarkably cre- combat rifleman, taught reading, writing the fall of 1964, stating, “I’m Redheffer, ative. For example, her meals were so and arithmetic to illiterate members of his and that’s no bull!” (4). (I was able to very creative, that the good news at platoon. It came to my father’s attention take math classes at UCLA, along with ­dinner was that a bad experiment in the that many soldiers could not write letters other high school students who lived kitchen was rarely repeated, although home from the front because they were near the campus.) the bad news was that a good experi- illiterate. For these soldiers, their loved I might have learned from these ment was also rarely repeated. But she ones were never sure whether they were math professors the key lessons about loved me, as she did all three of my sib- alive or not. So writing letters home was incorporating humor into teaching. lings. “Unconditional” and “­constant” an essential line of communication for I try to inculcate a good joke and describe my mother’s support and those on the front in ­combat. My father some irony into my lectures. For encouragement. helped these soldiers to communicate with example, I was asked to give a keynote My mother truly valued what we now families back at home and likely helped lecture at the Society of Neuro- call “thinking outside the box,” not only some of them learn to read and write. Oncology in San ­Antonio, just a short in the kitchen, but in her professional life. My father had a gift for humor. His walk from the Alamo. I based my Anne Steinman was particularly interested mathematics professor, Morris Kline, talk on an article that I wrote for in the field of early childhood develop- ment. She was a teacher and her specialty was early childhood education. She was one of the founding teachers in Head Start. She firmly believed that there were critical periods in development and that the nursery school years were of the utmost importance for educational development. A few years later, her interest in early development may have stimulated my interest in the work of Torsten Wiesel and David Hubel, who were studying critical periods in developing the visual system. My father, Norman, an immigrant from Russia, grew up in New York City. He was on his way to a brilliant career in mathematics as an undergraduate at NYU. He was President of the Mathe- matics Club there, and he graduated in 1939. My father and mother (who was born and raised in New York City) were Figure 1. My parents, Anne Steinman, right, and Norman Steinman, left, in 1939. From the married while my father was studying Steinman family collection.

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the Journal of Clinical Investigation entitled “No Quiet ­Surrender” (5), about the guardian ­molecules that protect the brain from various patho- logic attacks. The brain does have a remarkable capacity to withstand various types of attacks (5). In my lectures, my opening slide traditionally shows my beautiful campus at Stanford, juxtaposed with a landmark from the location where I am ­speaking. So as you can see in Figure 2, “No Quiet Surrender” is juxtaposed with the Alamo. I think the audience appreciated the connection. I often post my lecture on a webserver, and I advise individu- als that they can access my talk there. This particular lecture had quite a few uploads. My father’s career in mathematics was sidetracked by service in World War II. My sister, Louise, wrote a Figure 2. Poster for lecture at the Society of Neuro-Oncology, San Antonio, Texas, November remarkable memoir of my father’s 19, 2015. Humor is incorporated into teaching. A lecture on guardian molecules in the brain experience in World War II in her book is entitled “No Quiet Surrender” and is juxtaposed next to a picture of the Alamo. The ­Souvenir: A Daughter Discovers Her Father’s War (6). Louise’s book was reviewed in the New York Times, and Diane Cole wrote, “For Pvt. Norman Steinman, assigned to the 27th Infantry Regiment (the ‘­Wolfhounds’) of the 25th Infantry ­Division (the ‘Tropical Lightning’), the war, at its core, was horror: 165 days of continuous combat fought to reclaim from the Japanese the beaches, plains, mountains and caves of the Philippines” (7). After World War II, my father was interested in a career in medicine. With quotas for Jewish students in many of our medical schools, he entered phar- macy school and graduated in 1949. He owned a neighborhood pharmacy in Culver City. I worked there half a day on weekends as a teenager. Perhaps my small immersion in the neighborhood pharmacy taught me something about pharmaceuticals, and perhaps it inspired me to develop new pharmaceuticals in the setting of a small business. That idea—pharmaceutical entrepreneurship in a small business—became widespread as the biotechnology industry commenced Figure 3. Norman Steinman at work in the neighborhood pharmacy, where I worked half a generation later. Figure 3 shows my a day each weekend. From the Steinman family collection.

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father at the bench in his pharmacy on a probability and statistics and number Dartmouth in the spring of 1966. I wrote typical day around 1955. ­theory. There were high school students to Bronowski and asked him if it were Like his professor, Morris Kline, my from all over the country. I remember possible to work the next summer at father valued humor and used humor students from Boulder, Colorado; New Salk. Over Christmas vacation in 1966, in teaching all of us children some of York’s Bronx High School of Science; when I returned home from New Hamp- the lessons in life. Humor, as I have Meridian, Mississippi; and Snyder, Texas. shire to Southern California, Bronowski learned, is an important asset when The math institute was free and included invited me to La Jolla to visit the Salk facing the brutality of science, where tuition, room and board, and transpor- Institute. He took me on a half-day tour failure is common. In a life of science, tation. The program spawned numerous of the Institute, which had been just hypotheses frequently crumble in the professors of engineering and mathe- completed. He introduced me to many face of contrary data. Even after appar- matics, as well as lawyers, distinguished­ scientists. He assured me that he would ent success in a series of experiments, Air Force fighter pilots, and even at least arrange a job for me that ensuing­ sum- we still have to deal with peer review, one medical researcher from Culver City, mer. Then we had lunch in his backyard which is harsh and often seemingly California. on the Torrey Pines Mesa, near the unfair. I attended Dartmouth College and Institute. In our home growing up, each of majored in physics and minored in I remain grateful to Jacob Bronowski. us four children developed various Russian. The legacy of the Cold War He was so very humble, charming, streaks of creativity, probably kindled provided me with two more remark- and caring about my summer plans. by my mother. My sister, Ruth, despite able experiences. In 1966, I traveled to Although Bronowski was a ­celebrity— braces and numerous corrective Russia under the auspices of a State we remember him from the BBC series surgeries for her polio, was active in Department program, sponsored under The Ascent of Man—he went out of social organizations at school. Interest- the National Defense Education Act his way to help me, a young college ingly, her boyfriends and ultimately of 1958. This act was another reaction ­student. I have not forgotten this and her husband were strong and very to Sputnik, where the United States have strived to make sure that students athletic males. My younger sister, felt that it must “catch up” in science who ask me about research are given Louise, was an artist and a dancer and foreign language competency. opportunities to work in my laborato- and remains a gifted writer (6–8). My On my trip to Russia, we first spent ries at Stanford. Over the past 35 years, younger brother was a musician. There an intensive month on the campus of my lab has hosted well over 200 high were tight bonds between all of us sibs the University of Indiana. We spoke school and college students during the that have lasted. only Russian in our month in ­Indiana. ­summers, including three Intel Science We then went on a trip to Russia, Prize finalists. INFLUENCE OF RUSSIA’S SPUTNIK ON sponsored by the State Department. For the summer of 1967, I chose to MY EARLY SCIENTIFIC CAREER During that trip, I met many of my work in the laboratory of Ed Lennox, During elementary school, a memorable father’s aunts and uncles in Moscow who was a physicist turned biologist. event in the Cold War changed—for the and Kiev. The next summer, in 1967, Lennox was then working on a new better—the trajectory of my science educa- I had the good fortune to have my topic in immunology, the genetic tion. The Russians orbited the first satellite,­ first experience in the laboratory at the ­control of the immune response (10). Sputnik, in 1957, and as a result, the Salk Institute, which had just opened. Baruj Benacerraf had shown that the United States, under President Eisenhower My stipend for living and transporta- immune response to a hapten on a and then President Kennedy, supported a tion to the Salk Institute was covered synthetic polypeptide poly-l-lysine massive infusion of money to science edu- again under the same National Defense was under genetic control and could cation. Talk about timing and Lucky Larry! Education Act of 1958. be transmitted as a unigenic mende- In 1962, I spent a summer at a National I obtained the summer job at the lian trait (11). Sela and McDevitt had Science Foundation (NSF)-sponsored high Salk Institute in 1967 because of an just published their seminal paper school math institute in Corvallis, Oregon.­ encounter with Jacob Bronowski, who in 1965 in the Journal of Experimental I was able to track the NSF grant for was visiting Dartmouth. Jonas Salk Medicine (7), showing that antibody $21,560 for funding the Summer Math- envisioned that the institute bear- responses to the branched, multichain ematics Institute at Oregon State under ing his name would be a haven for synthetic polypeptide, poly (tyr,- mathematics professor, Robert Gaskell (9). not only science, but also for the arts glu)-poly DL-ala--poly lys, ((T,G)-A--L) Mathematics “geeks” from all across and philosophy (1). Salk hired Jacob and ((H,G)-A—L), a synthetic poly- the United States were taught by the Bronowski as the first philosopher­ in peptide in which histidine replaces Oregon State math faculty. We learned residence at the Institute. I had served tyrosine, were under strict genetic Fortran programming, Boolean algebra, as host for Bronowski when he visited control (12,13). Both Michael Sela and

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Hugh McDevitt were to play major ­Jakobsen’s talks on the origins of lan- “complex” or “hypercomplex” cells in roles in my career over the next 50 years. guage. In Renato Dulbecco’s lab, Andre their visual cortex (17). After recording The subject of the genetic control of Lwoff was a visitor and David Baltimore from these cells, we were supposed to the immune response to a component was a postdoc. Jonas Salk himself was inject them with a fluorescent tracer, so of influenza became a major focus of on the scene, and as you know, he had that we could then fix the brains and my own latest research, nearly half a iconic status in my family. A phone call formally identify the cells and correlate century later (14). home mentioning that I had passed Jonas their anatomy with the electrophysiology. My summer at the Salk produced Salk in the hallway was likely to elicit Whereas Jim Hudspeth was gifted in even more opportunities for Lucky a response from my mother about how many ways, including wonderful manual Larry than “just” an introduction to a fortunate Salk was to have me working dexterity, he could accomplish this formi- new field, the genetics of the immune in the Institute that summer. dable task; I found myself to be a laggard response. At the neighboring bench, In the Lennox lab that summer, Stephen in comparison, without such gifts. Jim a colleague of Ed Lennox was visiting Kuffler, who was Chair of the ­Department Hudspeth is a distinguished professor,­ the Institute from Cal Tech. Seymour of Neurobiology at Harvard, and two now at the Rockefeller. When my son was Benzer came to the Salk that summer, of his colleagues, David Potter and Ed interviewing for the MD, PhD, program from Cal Tech with his collection of Furshpan, had joined Lennox and Benzer at Rockefeller, he proclaimed that around Drosophila. He was trying to grow in attempts to grow synapses in ­culture. the dinner table when he was growing synapses from dissociated Drosophila I was welcome to attend their long up, his father (me!), would rarely discuss neurons. A problem arose for my own lunches and listen in on their discussions. the name Einstein. Instead, the name he research, because my key measurement It came to Stephen Kuffler’s attention heard most often associated with the term was a 12-h hemag­glutination assay to that I liked to play tennis. So every day “genius” was the name “Hudspeth!” (18). detect antibody to influenza, not to at 6:00 PM, I was chosen to be his tennis I was then asked to do another clumped Drosophila. Often at the end of opponent on the court behind the house experiment based on the finding by a 12-h incubation, all that appeared at he had rented that summer. Ted Geisel, Grafstein (19), that radioactive tracers the bottom of the titer plate was a dead Dr. Seuss, lived in the house neighboring could be used to map the visual path- fly. I confronted ­Professor Benzer after the court. “And to think that I saw it at the way. I was to repeat the classic Sperry a month of exasperation and asked him Salk Institute,” would have been a fully experiment on the specificity of axonal to keep his bottles of flies capped. He explicable extrapolation of Seuss’ first connections (20) and to trace retino-tectal jokingly grabbed me by my shirt collar book entitled, And to Think That I Saw It on connections in the goldfish after optic and told me something like, “calm down, Mulberry Street (16). nerve transection, followed by surgi- kid!” I was aware of Seymour’s prowess cal inversion of the retina. I was then from his phage work, from a genetics MEDICAL SCHOOL AND supposed to map the regenerating optic course in college. I had no idea that his POSTDOCTORAL STUDIES nerve fibers as they innervated the optic work would branch far beyond phage, to Following the theme of Lucky Larry, tectum. Although I had some success with help us understand the neurobiology of where one piece of good fortune leads these experiments, I could never provide love, time and even memory. Jonathan to the next, perhaps because of positive convincing enough data to publish. Nine Weiner’s brilliant biography captures ­recommendations from Lennox and years later, Sperry, Hubel and Wiesel the aspects of Seymour Benzer that I met Kuffler, I gained admission to Harvard shared the Nobel Prize in Medicine (21). that summer of 1967 (15). Medical School in 1968. A good slice My mother of course was certain when So Seymour Benzer capped his backhand in my tennis games against she read of the Prize in 1981, that it was flasks of flies, and I measured antibody Stephen Kuffler may have outweighed given to these distinguished scientists, responses to influenza, observing differ- some grades in statistical thermodynam- because I had worked with two of them ent levels of antibodies in mice with dif- ics at Dartmouth. as a medical student. Perhaps much closer ferent genetic backgrounds. Fifty years With an interest in neurobiology, I to what we call the “reason” that I chose later, I returned to the same subject, decided to spend a research year under to work with them, was my mother’s this time in humans, who developed a Professors Torsten Wiesel and David interest in early childhood development. neurologic disease after influenza immu- Hubel. In the Hubel and Wiesel labora- I did have some good fortune during nization, but only when they had certain tory, I was asked to perform some truly my research period with Torsten ­Wiesel. genetic backgrounds (14). “bold” experiments. First, a young med- While studying the goldfish retina But that was not all that came from ical student named Jim Hudspeth and using radioautography, with a gifted that remarkable summer. Remarkable I were independently asked to operate ­postdoc Dominic Lam, we were looking visitors lectured all week. I recall on cats and then to identify with electro- at the uptake of gamma-­aminobutyric Paul Berg’s talks on SV40 and Roman physiological recordings the “simple,” acid (GABA) in the ­goldfish retina.

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The uptake was regulated with ­activity. immune response in T cells and acted as Michael was extraordinarily responsive. A radioautograph of the ­retina, done an inhibitory signaling molecule in the On a steamy August day in Israel in 1972, while ­investigating uptake of ­tritiated immune system (24). I have remained a we sat in his office at the Weizmann GABA, with a flashing light as the longtime friend of Dominic Lam, who is Institute for an hour, discussing all the ­stimulus, revealed some stunning a polymath, a gifted artist and a biotech impressive projects that were ongoing ­morphology. The uptake resembled a entrepreneur. in chemical immunology, including a silver tracing of the horizontal elements in Before graduating from Harvard few that combined neurobiology and retina, first published by Ramón y Cajal Medical School and heading to Stanford immunology. He did mention work on a in 1909 (22). The pattern of GABA uptake for internship and training, I decided to peptide-based drug named Copolymer-1, is shown in Figure 4, which is reproduced explore immunology. I always had the which might someday become a thera- from the 1909 paper. The result was idea to combine my interests in neu- peutic in MS. Copolymer-1 was 1-year-old published in the Proceedings of the National robiology with immunology. In 1972, at that time and ultimately became the Academy of Sciences as David Hubel’s first I traveled to Israel and met with Michael best-selling prescription pharmaceutical contribution in 1971 (23). I was to return Sela, to discuss the possibility of doing for treatment of MS. to the study of GABA, 38 years later (24). a postdoctoral fellowship with him that Thus, before leaving Harvard, I We showed that GABA suppressed the combined neuroscience and immunology. contacted Baruj Benacerraf to do a

Figure 4. Radioautographs of the retinal uptake of GABA under illumination (23) reveal the horizontal cell networks in retina that Ramón y Cajal described in 1909 (22).

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tutorial in immunology in my last year, rabies vaccination (28), was critical for complex (MHC), myelin antigens and 1973. Benacerraf was responsive and the discovery of three therapeutics now the T-cell receptor, which had just been arranged for a weekly immunology approved and used widely in MS: glati- identified by Mark Davis and Tak Mak, tutorial for me with one of his impres- ramer, natalizumab and fingolimod. were involved in the pathogenesis of sive younger faculty members, Dr. Carl Glatiramer came directly from the EAE neuroinflammation (33). Mark Davis Pierce. With Carl, I learned about the model, where it was shown to prevent and had just arrived at Stanford, and the new and dazzling world of helper cells, reverse ongoing EAE (26,29). ­Natalizumab immunology world was electrified with haptens and carriers. I left Harvard was discovered in my laboratory in the discoveries emanating from Davis’ for Stanford in 1973 for my internship. early 1990s from an experiment where breakthrough. Hugh McDevitt and Len I can remember the dean of students, we sought to analyze the molecules and Lee Herzenberg were remarkably Joe Gardella, mentioning that by going involved in homing from blood to brain open and interactive during this part west, my decision would most likely (30,31). ­Fingolimod was saved from being of my career. Hugh McDevitt made mean that I would never get a job at shelved, after its disappointing effects in available his entire toolkit of antibod- Harvard. The dean at Harvard was cor- protecting from transplant rejection. It was ies to components of the MHC. With rect in that I never applied for a job at shown to be effective in EAE, and Novar- Ram Sriram and Jim Rosenbaum, now my medical school alma mater. For me, tis decided to develop the drug for a new professors at Vanderbilt and Oregon it was “California, here I come, right indication, relapsing remitting MS (32). Health Sciences University, respectively, back where I started from.” I returned to Stanford in 1977, with we published work on the suppression After finishing my internship in my Israeli wife, Chany, whom I met of paralysis in EAE with antibodies to surgery and doing 6 months of pediat- on the tennis courts at the Weizmann. MHC class II (34,35). We fully intended rics work, I headed to the Weizmann I completed a residency in neurology to develop this approach for clinical Institute in 1974. I was given a desk in over the next 3 years. In 1980, a fac- application and went as far as success- the ground floor of the Wolfson Build- ulty position was available, and I was ful tests in nonhuman primates (36). ing in a laboratory shared with the late appointed as Assistant Professor. Reports of toxicity when giving anti- Dvora Teitelbaum, who along with At Stanford, I aspired to try to be a bodies to HLA class II molecules in Michael Sela and Ruth Arnon, held “triple threat,” describing an academic nonhuman primate studies made us the original patent on the blockbuster, physician, who engaged in a clinical prac- reluctant to take this approach forward glatiramer: U.S. 3,849,550, “Therapeutic tice caring for patients, who taught med- in the clinic. Copolymer” (25). ical students and graduate students, and We also developed an approach to I spent three exciting years learning who did laboratory research. As it turned treating MS with an anti-CD4 anti- chemical immunology under Michael out, the beginning of the era of biotech- body. CD4 is the binding partner of Sela and Ruth Arnon and cellular immu- nology was upon us, and there was to be MHC class II. In a series of preclinical nology with Irun Cohen. I had an excep- a “fourth threat”: the merging of medical and clinical experiments, initiated by tionally wonderful mentorship with research with biotechnology companies. my first graduate student, Matthew Irun Cohen, who was a fellow clinician. Waldor, who is now himself a ­professor Every day after work, we would have EARLY YEARS ON THE STANFORD at ­Harvard Medical School, we showed a long run through the orange groves, FACULTY that an antibody to CD4 was potent after which we would have a beer and As a junior faculty member, I jug- and effective in reversing EAE (37,38). discuss science, philosophy and Jewish gled clinical duties for about 4 months By the time these experiments were history. All these faculty members at the a year on the Child Neurology service ready to be tested in the clinic, we were Weizmann Institute taught me how to as well as clinics in both child and adult reluctant to lower CD4 counts much think about how experimental results neurology. Fortunately, in those days, below 250/mm3 because of our aware- might be translated in the clinic. it was easy to get federal funding, and ness of the consequences of low CD4 At the Weizmann, I also was intro­ no one spent much time even worrying counts in HIV infections. Therefore, duced to the quintessential model of about the thresholds for success on grant when taken into the clinic, anti-CD4 experimental neuroinflammation, exper- applications. The focus of my work was did not meet its primary endpoints imental autoimmune encephalo­myelitis to try to understand the pathophysiology in relapsing remitting MS, although a (EAE), (26,27). I have written about of MS and to develop therapeutics to covariate analysis showed that relapse how the EAE model could be used to treat MS. rate and disability favorably correlated test potential new therapies in MS. The To develop new therapeutics for with reduction in the CD4 count (39,40). EAE model, first introduced in 1932 at treating MS, my research investigated how Had we reduced the CD4 count in MS to the Rockefeller Institute to study acute the elements of the tri-molecular com- levels comparable to what we routinely disseminated encephalomyelitis after plex involving major histocompatibility reduce the CD20 B-cell populations

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with anti-CD20 antibodies such as homing of lymphocytes to the brain was at devising a therapy that would target Rituxan (41), perhaps clinical “success” α4 integrin. Karin later became Chief the T-cell receptors involved in the patho- would have been attained. of Immunology at Israel’s Technion. genesis of a disease. For EAE, induced by The chimeric CD4 antibody that we Yednock, Karin and our team were able a small peptide, there is restricted T-cell tried in the clinic was developed and to block paralysis and brain inflam- receptor usage. We demonstrated that manufactured by Centocor. I served mation with an antibody targeting α4 antibodies to the variable region of the as an advisor to Centocor from 1987 integrin. After our 1992 publication in T-cell receptor involved in the recogni- to 1989, when I was asked to join their Nature (46), further preclinical studies tion and binding of the critical patho- board of directors. As a director of led by Brocke and Veromaa confirmed genic autoantigen reversed ongoing Centocor, I participated in many of the activity (47). Each stage of clinical autoimmune disease (53). the decisions in the successful devel- trials continued to reveal a potent clinical With an outstanding postdoc Jorge opment of anti–tumor necrosis factor effect with natalizumab blockade of α4 Oksenberg, now a professor at UCSF, (TNF) therapy with Remicade and integrin. Clinical relapses in MS were and with a renowned collaborator Claude in the development of anti-integrin reduced by over two-thirds, and inflam- Bernard from Australia, we also showed therapy with Reopro. I had the oppor- matory activity detected with brain that, even in lesions in MS brain, there tunity to make lasting friendships imaging was reduced about 90 percent. was evidence of restricted T-cell receptor with Marc Feldmann, Taini Maini An approved drug entered the market expression (54,55). Tomas Olsson and col- and Jim Woody during these exciting 12 years later (48–50). leagues took these results forward into the times (42). My time with Centocor I had worried about the consequences clinic, targeting T cells with VB5.2 T-cell was the first of many fruitful experi- of blocking homing to the brain (51). receptors. They substantially depleted ences with the emerging biotechnol- My main concern was the development T cells reactive to myelin basic protein that ogy industry. Over my career, I have of opportunistic infections if immune produced interferon (IFN)-γ (56). started or played a role as a director in surveillance of the brain was blocked. six companies so far. Within 3 months of approval, the first FURTHER RESEARCH AT THE WEIZMANN Our experiments exploring the cases of progressive multifocal leukoen- INSTITUTE pathophysiology of MS helped identify cephalopathy occurred in patients who From 1995 to 1999, I had a joint a key therapeutic target in MS. In the had been taking natalizumab for more appointment in the Department of early 1980s, our group followed the than 2 years. There have now been over Immunology at the Weizmann Institute, elegant studies of Ben-Nun, Cohen and 500 cases of progressive multifocal leuko- along with my appointment at Stanford. Wekerle, as we developed T-cell clones encephalopathy (PML) in patients taking In the Weizmann, I decided to do some that recognized myelin basic protein (43). natalizumab. The good news is that a test high-risk “moonshot” type projects. With My second PhD student, Scott Zamvil, to mitigate risk was developed, so that Ari Waisman, my laboratory in Israel who is now a professor at University we can reliably segregate individuals at began work on engineering a DNA of California, San Francisco (UCSF), risk from those who are virtually risk free vaccine encoding autoantigen, to tolerize showed that these T-cell clones could (52). At present, natalizumab is the stron- the immune system for autoimmune provoke relapsing remitting paralysis gest therapeutic available for relapsing diseases such as MS, type 1 diabetes with demyelination (44). With Jonathan remitting MS, and its main risk can be and rheumatoid arthritis (57,58). We also Rothbard, we began a collaboration that mitigated by a predictive test (52). began experiments on treating Huntington has continued for over 30 years, to map While we were performing the disease, where the protein, huntingtin, the precise epitopes recognized by these experiments leading to natalizumab, containing a ­polyglutamine repeat T-cell clones (45). Our studies with these we were also developing much more longer than 35 glutamines, causes a T-cell clones culminated in work looking specific therapies. These approaches, lethal disease. Our approach was to test at how these T cells traverse the endothe- we hoped, would be more specific than a competitive inhibitor of the enzyme lium and traverse from the circulation to the concept in natalizumab that blocked transglutaminase, which is activated in the brain. the migration of large portions of the the brains of patients with Huntington Our studies on T-cell migration to immune system, including T cells, B cells disease (59,60). the brain involved a tight collaboration and macrophages, to the brain. Work between Ted Yednock at a biotechnology from several laboratories, including ours, TRANSLATIONAL RESEARCH AT startup, Athena Neurosciences, and my showed that T-cell receptor use was STANFORD OVER THE PAST 20 YEARS laboratory at Stanford. In experiments quite restricted when the immune system Returning to Stanford, my colleague, with Yednock and a gifted postdoc- targeted a small portion of a protein, in PhD student then postdoc, Marcela toral fellow, Nathan Karin, we showed the context of a given major histocompat- Karpuj, showed that cystamine had a that the key molecule involved in the ibility complex. These experiments aimed beneficial effect in an animal model

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of Huntington disease. In addition to ­Baranzini (now a professor at UCSF), paralysis in EAE (74). Moreover, we inhibition of transglutaminase, treatment Dorothee Chabas (a remarkable neurol- could modulate EAE with various with cystamine induced various protec- ogist from France), and Jorge Oksenberg isoprenoids in the sterol pathway. tive molecules including HSP40 (60). Five (by then a professor at UCSF) were able We demonstrated that the isoprenoid other independent groups showed bene- to analyze the most prevalent transcripts geranylgeranyl-pyrophosphate (GGPP) fit in animal models with cystamine and in MS lesions. We found that aB crys- mediates proliferation, whereas both its simpler form cysteamine (61). Other tallin was the most prevalent transcript GGPP and its precursor, farnesyl-PP, protective molecules such as BDNF were in MS lesions. We did not study aB regulate the Th1 differentiation of induced with cystamine treatment (62). crystallin intensively for another 5 years, myelin-reactive T cells (75). We could This work has been taken forward and is because we focused some of these initial reverse the beneficial effect of atorvas- now in advanced clinical trials. studies on osteopontin (64–66). In a con- tatin with the isoprenoid intermediate Most of the efforts of the laboratory tinued collaboration with Renu Heller, farnesol (75). at Stanford over the past 35 years have with the able collaboration of Chris Lock, The role of statins in blocking the focused on understanding the pathogen- now a Professor at Stanford, we also mevalonate pathway was taken forward esis of MS (63). We also initiated studies studied lesion material with gene chips into clinical trials first by Zamvil and investigating the transcripts, proteins (67). This same material was the subject colleagues (76). Recently, encouraging and lipid molecules that are present in of proteomic studies with my colleague, results with treatment with statins in MS lesions. These studies have culmi- May Han (68,69). We also performed individuals with secondary progressive nated in five different clinical trials. lipidomic studies on MS material with MS were reported by Chataway and I shall describe the efforts we have taken Peggy Ho, my research associate for colleagues, where brain atrophy was from the bench into the clinic in MS and more than a decade; my colleague, Bill slowed when statins were given com- in another autoimmune disease, type 1 Robinson, now a leading faculty member pared with placebo (77). diabetes. at Stanford; and our joint PhD student, Working with Jennifer Kanter, Bill Our efforts at understanding the Jennifer Kanter (70,71). Robinson, Peggy Ho and Shannon Dunn, pathogenesis of MS were directed The role of osteopontin in MS was we investigated the roles of lipids in at studying MS lesion material itself quite intriguing. Two of the proteins MS further (71). Designing solid-phase obtained from rapid autopsies. I did not that bind osteopontin are VCAM and α4 arrays to detect the immune response want to participate in the large-scale integrin (63–66). In fact, the role of oste- to lipids followed naturally from work team efforts in genome-wide association opontin and integrin in the migration of we had done with myelin protein studies and decided instead to apply lymphocytes into the brain parallels the arrays in association with my Stanford emerging technologies to investigate metastasis of tumors from the blood into colleagues, Bill Robinson and PJ Utz well-defined lesions from MS. We col- solid organs. In a sense, the osteopon- (78). We discovered some fascinating laborated with Professor Cedric Raine at tin-aided migration of lymphocytes into short-chain fatty acids and phospholip- the Albert Einstein School of Medicine, brain via α4 integrin is indicative of how ids in the myelin sheath of patients with who had some remarkable pathologic the immune system gains access to brain. MS who had the remarkable­ feature material obtained with rapid autopsies. With my PhD student, Eun Mi Hur, now of attenuating­ neuroinflammation. These specimens were preserved in a researcher in industry, we showed that Remarkably, a component of the myelin a manner that allowed us to perform osteopontin can trigger clinical relapses sheath had evolved not only to serve as large-scale sequencing of transcripts, as in mice (65,66). Osteopontin levels are an insulator for the electrical response well as further analysis of the proteins elevated around the time of relapse in along axons, but may have coevolved and lipids in the same pathologic sam- MS (72,73). to provide protection against inflamma- ples. These investigations allowed us Further studies on MS pathogenesis tion in the brain (71). This result would to discover molecules that were quite focused on the roles of lipids in MS. exemplify how lipid components­ of the unexpectedly present in lesions. We then With Sawsan Youssef, now a researcher central nervous­ ­system have guardian used preclinical animal models, particu- in the pharmaceutical industry, and properties to attenuate inflammation (5). larly various versions of EAE, to under- Shannon Dunn, a professor at the aB crystallin was the most prevalent stand their potentialpathophysiologic­ University of Toronto, we studied the transcript (64) in our study of promi- roles. role of farnesylation and geranylation nent mRNAs in MS lesions. Van Noort In a wonderful collaboration with on the inflammatory response in MS. In (79) demonstrated that an immune Dr. Renu Heller, then at Roche, we a series of papers done in collaboration response to aB crystallin was present gained access to a robotic sequencer with Scott Zamvil, now a professor at in MS patients. He eluted antigens around the year 2000 for these studies. UCSF, Youssef and Dunn showed that from myelin from an MS brain and By using cDNA libraries, Sergio atorvastatin was effective in reversing asked which fraction most prominently

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stimulated lymphocytes from MS proteins (either cryab or β-amyloid established a company, Transparency patients. He found that aB crystallin peptides 1–40 or 1–4), EAE improved, Life Sciences, to disrupt traditional was a stronger antigen and stimulated whereas in loss-of-function experi- ­pharmaceutical development. Using MS T cells to a greater degree than ments, amyloid knockouts had worse crowd sourcing to help design the well-known myelin proteins (79). We EAE. These results were surprising, ­clinical trial, we obtained an investiga- tested whether injection of aB crys- since most investigators had assumed tional new drug (IND) designation from tallin (cryab) would modulate EAE that amyloid proteins worsened or the FDA and have begun a clinical trial, and, to our surprise, Shalina Ousman provoked neuroinflammation. sponsored by the National Institutes of (now a professor at the University Meanwhile, Rothbard and another Health, with Professor Fred Lublin at of Calgary) who led these studies outstanding postdoc, Mike Kurnellas, Mt. Sinai School of Medicine in New showed that intravenous injection of had done structure function experiments York (95). cryab suppressed ongoing EAE. She narrowing the domains of amyloid One of the biggest challenges in the also demonstrated that cryab sup- proteins that might exert their immune-­ field of MS is our lack of understanding pressed the p38 MAP kinase pathway, suppressive activity (89,90). Finally, of why females are more susceptible a vital component of the inflammatory Rothbard and ­Kurnellas realized that than males to this disease. This female- response. Surprising to us at the time Eisenberg’s amyloid fibril hexapeptides to-male disparity is even more pro- cryab–/– mice had more severe paralysis might indeed have immune-suppressive nounced in other autoimmune diseases and more extensive inflammation in the properties. In a 2013 article, we showed such as systemic lupus erythematosus EAE model (80). that ­hexapeptides that formed amyloid and neuromyelitis optica. Shannon We noted that cryab was beneficial in fibrils would suppress ongoing EAE. We Dunn tackled this problem while a other diseases including stroke (81), myo- showed that hexapeptides derived from postdoc and has continued her bril- cardial infarction (82) and ischemic optic β-amyloid, tau, prion protein, amylin liant work in a faculty position at the neuropathy (83). The penumbra of stroke and cryab all suppressed EAE (91). ­University of Toronto. We published a was greater in cryab–/– mice (81). Jonathan Three mechanisms are elicited series of reports in the Journal of Exper- Rothbard, with whom I’ve collaborated when amyloid fibrils are injected. The imental Medicine and Nature Medicine for 30 years, informed us that David amyloid structures bind inflammatory (96–98) describing the role of peroxi- Eisenberg at UCLA had demonstrated mediators in plasma (89–91). Amyloid some proliferator–­activated receptor that cryab is an amyloid structure and hexapeptide structures elicit a type 1 (PPAR)-α and PPAR-δ in regulating the that it formed amyloid more slowly than interferon response (93). Most recently, sexual dimorphism. PPAR-α is overex- other more notorious amyloid proteins we showed that these amyloid hexa- pressed on male T cells. Knockout of such as tau, prion protein, amylin and peptides induce immune-suppressive PPAR-α restored high susceptibility to β-amyloid. Moreover, Eisenberg and col- B-1a regulatory cells, which secrete EAE. Androgens drive PPAR-α, and leagues had shown that there was a min- interleukin (IL)-10 (91). they bias the immune response toward imal hexapeptide motif in these ­proteins Our proteomic studies elucidated Th17. Female immune responses are that had sufficient energy to form β zipper other molecules of interest in MS tilted to Th1 with the dominance of structures and amyloid fibrils (84,85). lesions. As an example, we found IFN-γ, whereas male responses are An entrepreneurial PhD student, evidence of angiotensin receptor in MS pushed to Th17, dominated by IL-17 Jacqueline Grant, had shown that lesions in our proteomic studies (69,94). and IL-23. Dunn showed that this injection of β-amyloid peptides 1–40 Peggy Ho, Tobias Lanz and Michael was true across species from mice to or 1–42, thought to be pathogenic in Platten, now a professor in Heidelberg, humans (97,98). Because PPAR-α is Alzheimer’s disease, were capable took this information and showed that targeted by widely used drugs such as of suppressing EAE (86). Moreover, we could reverse ongoing paralysis in gemfibrozil, this dimorphism provides amyloid precursor protein knockout the EAE model with standard dosing clues that can be translated to therapy mice (APP–/–) had worse EAE (86). This of lisinopril (94). Lisinopril inhibited with widely used approved drugs for result was therefore the second exam- inflammatory signaling through Stat1 other indications. ple of worsened EAE with a knockout and Stat4 and induced T regulatory Perhaps the primary goal in my of an amyloid-forming protein. We cells (94). It was a challenge to find research over the past decade is to had shown in Ousman’s work that a pharmaceutical partner to sponsor translate the concept of antigen-specific cryab–/– had worse EAE (80) and larger clinical trials in MS with a drug used tolerance to the clinic. If you give any strokes (81). Others had shown worse by millions for hypertension and that respectable immunologist the task of EAE in tau–/– mice (87) and in Prp–/– was generic. So in collaboration with tolerizing an ongoing immune response mice (88). Thus, with gain-of-function entrepreneurs, transplant surgeon to protein X in an experimental animal, experiments injecting amyloid-forming Tomasz Sablinski and Marc Foster, we most of us can achieve this goal with

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a number of well-tested interventions sensible choice to target in inducing endpoints were attained on reduction of including low-zone and high-zone tolerance. Such a driver clone usually gadolinium-enhancing lesions (p < 0.05). would recruit other T 1 clones, so tolerance, presentation of antigen in a H At the 0.5-mg dose, 23 anti-myelin controlling the driver may effectively different format (such as coupling the close down the response. However, it antibodies including anti–myelin basic antigen to cells), and so forth. Remark- is also likely that a dominant, small protein epitopes were reduced in the ably, we do not have any approved set of driver clones exists for each anti- CSF, again demonstrating the contraction antigen-specific tolerization thera- gen in the target organ, so it would of epitope spreading of the antibody pies for any autoimmune disease in be an advantage to tolerize each of response, similar to what was seen them. Maximum security from autoim- humans. munity would be predicted when the in the phase 1 trial (101). One of the At the turn of the 20th century, Bill crucial drivers, as well as their major major issues in MS is whether immune Robinson, PJ Utz, Hideki Garren and recruits (to ‘spread determinants’), are responses to MBP are key drivers of disease. I earnestly began a program to try to all tolerized. This is the tack pursued I think not, and in 2016, we are not really et al. tolerize to antigens in experimental by Robinson , where the DNA certain of the key targets of the adaptive encoding each of the antigens whose ­autoimmune disease. We chose as our specific T cells are easily recruitable immune response in any form of MS. “platform” the DNA plasmid approach, is used in a tolerance-inducing reg- We made another effort in the field of since we could shuttle into the coding imen to ask whether the number of type 1 diabetes. Thanks to the pioneer- region of the plasmid the cDNA for disease relapses usually found in auto- ing work of the late George Eisenbarth, the protein antigen of choice. We also immune animals can be reduced (103). we have a rather strong understanding engineered the backbone of the plasmid of the islet antigens that the immune so that we would replace proinflam- Garren, Robinson, Utz and I formed system attacks in individuals with type matory noncoding CpG (5′—C—­­ a biotechnology company, Bayhill 1 diabetes (104,105). Proinsulin is at the phosphate—G—3′, cytosine and guanine Therapeutics, and licensed the technol- top of the list of antigens that are targets separated by only one ­phosphate) motifs ogy we had developed from Stanford of the autoimmune response in type with an alternative GpG (5′—G—­­ University. With Bayhill, we translated 1 diabetes (104,105). In a detailed series phosphate—G—3′, ­guanine and guanine these experiments into two notable of preclinical experiments, we identified separated by only one phosphate) motif. clinical trials: one in relapsing remitting proinsulin as the key antigen targeted Paulo ­Fontoura, Peggy Ho and Hideki MS (100,101) and a second in type 1 in the NOD model of type 1 diabetes. At Garren were instrumental in devising the diabetes (102). In MS, we were asked by Bayhill Therapeutics, Nanette Solvason, GpG motifs and engineering them into the FDA to try antigen-­specific toler- Michael Leviten and Hideki Garren the plasmid backbone. ance with one antigen. Our engineered revised the tolerizing plasmid further Our first efforts were in the EAE plasmid encoded myelin basic protein. with addition of a chimeric intron to model of neuroinflammation and Phase 1 and phase 2 trials indicated increase expression and designed a non- the NOD model of type 1 diabetes that we were achieving antigen-­specific secreted version of proinsulin, localizing (78,99–102). In these models, we achieved tolerance. In phase 1, we showed with proinsulin to intracellular sites (106). ­success in both prevention and ­reversal a carboxyfluorescein succinimidyl ester In an 80-patient, placebo-controlled, of disease. We created large-scale arrays (CFSE) assay that we were able to clinical trial, aimed primarily at safety, to follow the intramolecular and intermo- reduce the number of IFN-γ–­producing we showed that the approach was safe. lecular epitope spreading (78). Reversal T cells that proliferate in response We demonstrated that there was actu- of paralysis in the EAE model indicated to myelin basic protein, by using a ally increased production of C-peptide that we not only could deal with the dye-­dilution–based flow cytometric during dosing. There were indications issue of epitope spreading, but when we assay (100). of benefit in A1c hemoglobin and in tolerized to key “drivers” of the immune We next did a phase 2 trial in 267 insulin usage (102). I should remind response, we could observe “epitope patients with relapsing remitting readers that it was Tony Cerami who contraction,” the opposite of epitope MS (101). The primary end point in elegantly showed that A1c hemoglobin spreading (78,101). the phase 2 trial was the 4-wk rate levels correlated with glucose control in In an editorial that accompanied a of occurrence of new gadolinium-­ diabetes (107). In this study, we collabo- 2003 paper in Nature Biotechnology (78), enhancing lesions on brain magnetic rated with Professor Bart Roep in Leiden the “father of epitope spreading,” the resonance imaging from wks 28 to 48. to demonstrate that ­antigen-specific late Eli Sercarz wrote: No major safety issues were seen. The tolerance to proinsulin was attained. The primary endpoint was nearly at­- specificity was important because there One relevant principle that has emerged tained with a reduction in gadolinium-­ was no diminution in CD8 reactivity is that once a ‘driver’ T-cell clone (or enhancing lesions at 44 wks (p < 0.07) at to viral antigens such as EBV and CMV clones) is established, it becomes the the 0.5-mg dose, and several secondary (102). Plans for the next trial with 52 wks

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of dosing of the tolerizing plasmid are vaccines and mimics the receptor for I often think of the cliché about underway, including preliminary discus- orexin in the brain. The orexin recep- “searching for the lost key under the sions with regulatory agencies. In the tor is intimately involved in sleep and lamppost.” On a recent hike to a prom- next trial, we plan to test the vaccine feeding behavior (14). The intersection ontory above the town where I grew up, in children with type 1 diabetes, soon of the brain and the immune system, Culver City, I found a remarkable place after diagnosis. Further optimization of and the genetic control of the immune for “looking under the lamppost.” In our the approach is possible in the future, response apparently recurs in my life in city’s yard for public works, there is a including the use of plasmids encoding research. whole depot of lampposts (see Figure 5). other islet antigens, including glutamic Perhaps if one is looking for a lost key, one acid decarboxylase (108). SUMMARY should go to a depot that is full of such Another area of focus for our group I have tried to recount the history lampposts. May I suggest that a trove was an attempt to use various pro- of what we have done in the labora- of exciting data is under the lamppost, teomic and genomic technologies to tory over the past 50 years. The story but you might want to explore where predict what therapy might be used is perhaps full of too much detail for lampposts may be concentrated, not just optimally in diseases such as MS, where the casual reader. Therefore, in this under one such post. Exciting discoveries we have 10 or more approved drugs. conclusion, I try to list some important lurk in anomalous data, which might be A set of biomarkers based on a mea- lessons that I have learned in the past considered a repository of “lampposts.” surement of blood is perhaps the most ­half-­century in research. practical approach. This result has been Compliment Your Colleagues achieved once before in predicting how Learn from “Apparent Failures” Complement has a major role in both to mitigate risk when using natalizumab Tony Cerami wrote a brilliant essay, the immune system and the nervous (52). Investigations over the past 7 years, “The value of failure: the discovery of system (113). It may be time to remind led by Robert Axtell (a postdoctoral TNF and its natural inhibitor erythro- ourselves that it is a good idea to send fellow in my lab and then a faculty poietin” (110). What may appear as a compliments. We spend a great deal of member at Oklahoma Medical Research “failed” experiment may actually be time as working scientists acting as “tough Foundation), have stratified the differ- a piece of anomalous data, for which peer reviewers.” I recommend sending ent clinical types of the disease we lump significance is even more important a colleague a compliment on an exciting together as relapsing-remitting MS. than the data one is seeking based on paper or a fine lecture, even if you may Axtell and colleagues use a combination the hypothesis. Two obvious exam- be jealous of their ­achievement. Sending a of cytokine and chemokine profiles on ples of turning “failures” (lemons) into compliment once in a while might condi- serum and then advanced bioinfor- successes (lemonade) are seen in my tion us to be more humane when we enter matics. We demonstrated that there is research. In 2000, we published that our the role of “peer reviewer.” heterogeneity in the levels of a battery attempts to use altered peptide ligands of cytokines and chemokines in indi- in MS to tolerize the immune response Teach viduals with relapsing-remitting MS, to myelin was fraught with problems. Teaching medical house staff, teaching and the levels provide a signature that Our work showed that pushing a Th1 graduate students and teaching colleagues correlates with the therapeutic response response toward Th2 created the risk is a wonderful way to learn. Questions to IFN-β (109). of anaphylaxis. The clinical trial that raised by students are often effective chal- One other area of intense interest we reported was discontinued because lenges that give us new insights. One of in the past decade of my research ties of this safety risk (111). A few years my most pleasurable experiences at Stan- together with the first experiment that later, Rosetta Pedotti, Steve Galli and ford was to teach a course with a gifted I performed at the bench 50 years ago I showed that it was possible to induce colleague, Sara Brownell, on the brain and at Salk under Professor Lennox. There anaphylaxis to self-antigens (112). Thus, the immune system. I looked at the genetic control of the Ehrlich’s vision of Horror Autotoxicus immune response to influenza. In a (111) became reality. Another clear Write and Communicate wonderful collaboration with Dr. Sohail example of learning from a “failure” I think that the American public is in Ahmed, then at Novartis Vaccines in follows from our work showing that general rather ignorant about science, Siena, Italy, we studied how a ­particular amyloid proteins do not worsen neu- including the subjects of the brain and influenza vaccine in 2009 triggered narco- roinflammation. Instead, we showed the immune system. Part of the problem lepsy in individuals who were HLA-DQ that amyloid structures are strongly has been our reluctance to write about 0602 (a gene locus in HLA). The research antiinflammatory, opening a whole new what we do for the lay public. The main showed that there is a component of the concept for amyloid in neurodegenerative graded exercise in the course on the brain influenza virus that is contained in some disease. and the immune system that I taught

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are worth trying to answer (115). These individuals are among my most eloquent teachers and scientific colleagues. To mix a metaphor about a disease of the brain with an allusion to another organ, these colleagues with MS have “skin in the game.”

Keep Spirits High with Humor and Self-deprecation As mentioned earlier, my father’s teachers, such as math professor Kline, and my father himself, made it clear that we must keep a sense of humor as we approach life. This advice applies to even serious efforts in fields like math and translational medicine. Professional life is full of setbacks. So I recommend keeping spirits high with humor. One of my ­colleagues who employed per- haps the most charming, intelligent and insightful use of humor has been Robert Axtell (109). Here I want to express my deep appreciation for my wife of the past 15 years, Lucy. She and I have known each other since childhood. She heard me speaking of endorphins and coined the Figure 5. Lampposts in Culver City, California, Department of Municipal Works. The best term “endoLphins.” This concept exem- place to find lost keys is under an entire depot full of lampposts. plifies an aspect of our brain’s chem- istry that may generate the joy that ensues from a career in translational with Sara Brownell (who is now on the Patients have poked fun at me, asking medical science. Finally, as I started this faculty in science education at Arizona “could I be one of your experimental article, I repeat here in conclusion, that State) involved writing short pieces. We animals that was cured of EAE?” I it has been a privilege to work on the alternated between communication to really take these comments to heart. If subjects of immunology and the brain, scientists in other fields with an article and when possible, we really need to and that I have been one Lucky Larry. similar to a “nature news and views” advance work to clinical trials. Transla- piece, with portions directed to the lay tional research requires a diverse team, DISCLOSURE public, as we find in the science sections and one should realize that it is not The authors declare that they have no of our newspapers and general maga- possible to have real expertise across competing interests as defined by Molecular zines. Brownell and I wrote, “incorporat- the wide swathe of fields necessary Medicine, or other interests that might ing formal communication training into to go from the bench to the bedside. be perceived to influence the results and undergraduate and graduate curricula for Therefore, teamwork and cooperation discussion reported in this paper. aspiring scientists will enhance the qual- are essential for translational medicine. ity of discourse between scientists and I should note that many members of the lay public” (114). We should work to my team either have MS themselves or REFERENCES improve our ­communication skills. have a family member that has been 1. Jacobs CD. (2015) Jonas Salk: A Life. New York: afflicted. Some of my colleagues, who Oxford University Press. pp. 559. Take Discoveries Forward to the have coauthored papers with me, are 2. Steinman L. (2013) The road not taken: ­antigen-specific therapy and neuroinflammatory Clinic With a Team not formally trained in research, but disease. JAMA Neurol. 1:1–2. My mother-in-law once scolded me for because they have MS, they actually ask 3. Kline M. (1956) Mathematics texts and teachers: a curing too many mice of experimental MS. the ­toughest ­questions—questions that tirade. Mathematics Teacher. 49:162–172.

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Cite this article as: Steinman L. (2016) ­A journey in science: the privilege of exploring the brain and the immune system. Mol. Med. 22:99–114.

114 | Steinman | MOL MED 22:99-114, 2016