# Lawrence Steinman

Lawrence Steinman is an American neurologist, neuroimmunologist and an academic. He is a Professor of Neurology and Neurological Sciences and Pediatrics at Stanford University.
Steinman's research has focused on how the immune system attacks the brain, specifically in cases of multiple sclerosis (MS), motor neuron disease (ALS), and neuromyelitis optica (NMO). He discovered the target for the first approved MS therapy using a monoclonal antibody and his work has elucidated how the Epstein-Barr virus (EBV) triggers MS. His laboratory at Stanford published research leading to the first approved monoclonal antibody therapy for MS, Natalizumab (Tysabri), and clarified the molecular basis for how EBV triggers MS. He has received awards, including the John Dystel Prize, the Charcot Prize for Lifetime Achievement in MS, and the Cerami Prize for creating a new field of research and contributing to disease prevention and treatment. He has also twice been awarded the Senator Jacob Javits Neuroscience Investigator Award by the National Institute of Neurological Diseases and Stroke.
Steinman is an elected member of the US National Academy of Sciences, and the US National Academy of Medicine.

## Early life

Steinman was born in Los Angeles and grew up in Culver City, California. His mother, born in Brooklyn, was the daughter of immigrants from the Pale of Settlement, while his father immigrated from the Zhitomir area in Ukraine around 1921. After World War II, where his father served in combat in the Philippines, his parents settled in Los Angeles, raising their four children near his father's pharmacy, where he worked part-time during high school. Working in the neighborhood pharmacy helped spark his interest in medicine. His sister's battle with poliomyelitis in 1951 influenced his focus on inflammatory brain diseases. He gained early lab experience at the Salk Institute working alongside Jacob Bronowski, Jonas Salk, Seymour Benzer and Stephen Kuffler to research the genetic control of immune responses to viruses.

## Education

Following the launch of Sputnik, the U.S. invested heavily in science education, providing Steinman with opportunities in math and physics, including a summer program at Oregon State University sponsored by the National Science Foundation. He attended Dartmouth College, graduating in Physics, and then pursued his MD at Harvard Medical School. He furthered his training as a post-doctoral fellow in chemical immunology at the Weizmann Institute of Science in Israel.

## Career

Steinman joined Stanford University Hospital as a resident in pediatric and adult neurology before joining the faculty in 1980. In the biotech industry, he co-founded Neurocrine Biosciences in 1990. From 2018 to 2022, he chaired the Research Advisory Committee on Gulf War Illness for the US Veteran's Administration. His contributions include chairing the Interdepartmental Program in Immunology at Stanford for 10 years and co-founding companies, including Bayhill Therapeutics (Tolerion), Nuon Therapeutics, Transparency Life Sciences, Pasithea Therapeutics, and Atreca. He holds several patents in immunology and therapies that target MS, Huntington's disease, ALS, and Type 1 diabetes.

## Research

Steinman has focused his research on the pathogenesis of multiple sclerosis and related neuroinflammatory diseases, as well as the development of antigen-specific tolerance therapies for autoimmune conditions such as type 1 diabetes and neuromyelitis optica. His laboratory also investigates the role of amyloid structures in diseases like MS, Huntington and Alzheimer.

### Multiple sclerosis therapeutics

Steinman was a senior author of the 1992 Nature article that identified α4 integrin's crucial role in brain inflammation, emphasizing its role in lymphocyte homing to the MS-affected brain. Using microarray analysis, he identified distinct transcriptional profiles between acute and chronic MS lesions, pinpointing key inflammatory cytokines and differentially expressed genes. He continued this analysis of MS brain tissue to identify critical proteins, sugars and lipids involved in acute and chronic pathology in MS brain. These studies on MS brain lesions identified guardian molecules that protect MS brain from injury. Furthermore, he was the global chief investigator on two Phase 3 clinical trials with glycoengineered monoclonal antibodies targeting B cells.

### Immunological mechanisms and therapeutic strategies

Steinman has conducted various studies on immunology to develop novel therapeutic strategies. While conducting research on the roles of lipids and proteins in MS lesions, he uncovered protective fatty acids and phospholipids, and highlighted αB crystallin as a prevalent transcript with potential as a therapeutic target with guardian properties. His work led to several clinical trials, including an investigation into antigen-specific tolerance for MS, where an engineered DNA plasmid encoding myelin basic protein showed promising results in a phase 2 trial. He also demonstrated that T-cell receptors are highly restricted in targeting specific protein segments presented by major histocompatibility complex molecules.
Steinman's research into the higher prevalence of autoimmune diseases in females revealed the roles of peroxisome proliferator-activated receptors (PPARs) and sex hormones in regulating immune responses. His studies on amyloid fibrils showed that fibrils, such as those derived from β-amyloid and αB crystallin, can suppress inflammation and autoimmune responses.

## Awards and honors

* 2004 – John Dystel Prize, National Multiple Sclerosis Society
* 2009 – Elected, National Academy of Medicine
* 2011 – Charcot Prize for Lifetime Achievement, International Federation of Multiple Sclerosis Societies
* 2015 – Elected, National Academy of Science
* 2016 – Cerami Prize, Feinstein Institutes for Medical Research
* 2023 – Pioneer in Medicine Award, Society for Brain Mapping & Therapeutics

## Selected articles

* Yednock, T. A., Cannon, C., Fritz, L. C., Sanchez-Madrid, F., Steinman, L., & Karin, N. (1992). Prevention of experimental autoimmune encephalomyelitis by antibodies against α 4 β l integrin. Nature, 356(6364), 63-66.
* Steinman, L. (2012). The discovery of natalizumab, a potent therapeutic for multiple sclerosis. The Journal of Cell Biology, 199(3), 413. doi: https://doi.org/10.1083/jcb.201207175
* Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., ... & Steinman, L. (2002). Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Medicine, 8(5), 500-508.
* Ousman, S. S., Tomooka, B. H., Van Noort, J. M., Wawrousek, E. F., O’Conner, K., Hafler, D. A., ... & Steinman, L. (2007). Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature, 448(7152), 474-479.
* Han, M. H., Hwang, S. I., Roy, D. B., Lundgren, D. H., Price, J. V., Ousman, S. S., ... & Steinman, L. (2008). Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature, 451(7182), 1076-1081.
* Ho, P. P., Kanter, J. L., Johnson, A. M., Srinagesh, H. K., Chang, E. J., Purdy, T. M., ... & Robinson, W. H. (2012). Identification of naturally occurring fatty acids of the myelin sheath that resolve neuroinflammation. Science Translational Medicine, 4(137), 137ra73-137ra73.
* Rothbard, J. B., Kurnellas, M. P., Ousman, S. S., Brownell, S., Rothbard, J. J., & Steinman, L. (2019). Small heat shock proteins, amyloid fibrils, and nicotine stimulate a common immune suppressive pathway with implications for future therapies. Cold Spring Harbor Perspectives in Medicine, 9(7), a034223.
* Steinman, L., Fox, E., Hartung, H. P., Alvarez, E., Qian, P., Wray, S., ... & Cree, B. A. (2022). Ublituximab versus teriflunomide in relapsing multiple sclerosis. New England Journal of Medicine, 387(8), 704-714. doi: 10.1056/NEJMoa2201904.
* Lanz, T. V., Robinson, W. H., Ho, P. P., & Steinman, L. (2023). Roadmap for understanding mechanisms on how Epstein–Barr virus triggers multiple sclerosis and for translating these discoveries in clinical trials. Clinical & Translational Immunology, 12(2), e1438. doi: 10.1002/cti2.1438.
* Chiot, A., Roemer, S. F., Ryner, L., Bogachuk, A., Emberley, K., Brownell, D., ... & Ajami, B. (2023). Elevated α5 integrin expression on myeloid cells in motor areas in amyotrophic lateral sclerosis is a therapeutic target. Proceedings of the National Academy of Sciences, 120(32), e2306731120.