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A common perception among physicians is that new medical knowledge usually moves from “bench to bedside,” that is, from laboratory experiments to clinical care. However, in many instances progress has occurred in the other direction, from bedside to bench, beginning with clinical observations. This has been the case for multiple sclerosis (MS), one of the important success stories of modern molecular medicine.
The development of highly effective B cell therapeutics for MS has produced substantial gains for patients with MS, many of whom can now reasonably expect lives free from disability, and has fundamentally reshaped the understanding of pathogenesis of an autoimmune disease that affects nearly 1 million individuals in the US.1 Multiple sclerosis is a demyelinating disease of the central nervous system (CNS) consisting of 2 distinct but overlapping components, early relapses mediated by inflammation, and late progression due to neurodegeneration.
The trail of discovery began with a clinical question: Why did the widely used model for MS—acute experimental autoimmune encephalomyelitis in rodents—produce a pattern of tissue damage so different from the distinctive changes of human MS observed in biopsy tissue obtained from patients? Sharply-demarcated white matter lesions with marked vesicular disruption of the myelin sheaths is the hallmark of MS, whereas typical experimental autoimmune encephalomyelitis is characterized by only limited myelin damage without vesicular change. It had been known since the late 1960s that experimental autoimmune encephalomyelitis could be adoptively transferred by brain–homing T lymphocytes. By extension MS was considered a “prototypic” T-cell–mediated disease, a concept that persisted even though an abnormal and highly focused humoral immune response in the nervous system was known to be characteristic of MS, and oligoclonal bands representing antibody clones present in spinal fluid but not the circulation had been used in diagnosis for more than a half century. Even the direct demonstration that T-cell–based therapies had no measurable effect on MS did little to change the concept that T cells cause MS.
The problem was solved with the development of a new disease model that exactly recapitulated the pathology of human MS2; the demonstration that adoptive transfer of T cells produced changes of rodent experimental autoimmune encephalomyelitis but that cotransfer of antibodies was required for MS-like pathology3; the direct identification of autoantibodies and B cells in MS tissue4; and the launch of clinical trials with anti-CD20 B-cell–targeted monoclonal antibodies. The trials, first with rituximab,5 then ocrelizumab,6 and recently ofatumumab, revealed near-complete—up to 99%—elimination of new plaques, focal areas of inflammation and demyelination responsible for MS relapses, an effect size unique in the history of neurologic therapeutics, and also the first approach to improve, albeit partially, the course of the most debilitating form of the disease, progressive MS.7 Benefits of therapies were present almost immediately, indicating a direct effect on B cells rather than on antibody products of plasma cells, likely due to interference with antigen presentation or cytokine secretion by disease–associated B cells.8
The concept of B-cell mediation of MS was initially greeted with skepticism by the academic community. However, proof-of-principle studies led to pivotal trials, global approvals by regulatory agencies, and major changes in the treatment of MS. Both translational and clinical research has now been recast, focused on B cells as mediators of both aspects of MS: inflammation and neurodegeneration. Clinicians and investigators arrived at a unitary view of the disease: by eliminating relapses, it became clear that clinically silent progression is present from inception and throughout the course of the disease; that peripheral B cells are responsible for relapses, while sequestered B cells within the CNS contribute to progression; and that long-lived, clonally restricted, memory B cells that produce oligoclonal bands and recognize diverse antigenic targets form an active immune axis in MS, trafficking between the nervous system and periphery.9
The MS relapse is becoming a problem of the past. In the clinical setting, treated patients are now estimated to have only 1 relapse nearly each quarter century.10 The disease is not cured, and despite the partial response of progressive symptoms to B-cell therapy, this component of MS remains a challenge. However, recent data justify optimism. Patients involved in the ocrelizumab clinical trials who received higher effective doses of the drug had less progression, suggesting that by targeting CNS B cells more effectively, progression might also come under full control.
Three clinical observations drove progress: modeling the true pathology, linking CNS B cells to oligoclonal bands, and observing the immediate effects of B cell depletion on disease. Each observation resulted from direct examination of patients or their tissues, and each changed the landscape of subsequent laboratory research.
Conceptual advances in medicine proceed from bedside to bench as often as from bench to bedside. Physician-scientists who remain clinically active and who can connect patients with investigation on a daily basis serve an essential, irreplaceable role in discovery. Yet, at many academic institutions, physician-scientists encounter challenges in the clinical arena, with its fast pace and seemingly unquenchable demands: regulations, documentation, work relative value unit quotas, and the like, and as “part-time” clinicians, they may be less efficient. However, physician-scientists represent the opportunity to connect biomedical research with patient care, enriching both worlds. For physician-scientists, providing time for contemplation and deep dives into unsolved clinical problems is as essential for discovery at the bedside as it is at the bench. Engineering clinical environments that support and encourage clinician investigators should be a high priority; even small modifications that are neither difficult nor costly, such as purchasing time for physician-scientists to have lighter outpatient schedules and rewarding supportive inpatient units and outpatient clinics, could help reinvigorate science at the bedside.
The value and importance of direct clinical observation is as important as ever. To advance progress against disease, it is critical to support a cadre of well-trained individuals who can move on a daily basis between clinic and laboratory, connecting and enriching both worlds.
Corresponding Author: Stephen L. Hauser, MD, UCSF Weill Institute for Neurosciences and Department of Neurology, University of California, San Francisco, 675 Nelson Rising Ln, NS-213, San Francisco, CA 94158 (email@example.com).
Published Online: May 7, 2020. doi:10.1001/jama.2020.1522
Conflict of Interest Disclosures: Dr Hauser reported that he serves on the board of directors of Neurona; serves on the scientific advisory boards of Alector, Annexon, Bionure, and Molecular Stethoscope; and has received nonfinancial support from F. Hoffmann-La Roche Ltd and Novartis AG.
Funding/Support: This work is supported by grants R35NS111644 from the National Institute of Neurological Disorders and Stroke and RR 2005-A-13 from the National Multiple Sclerosis Society, and the Valhalla Foundation.
Role of the Funder/Sponsor: The sponsors had no role in preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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Hauser SL. Progress in Multiple Sclerosis Research: An Example of Bedside to Bench. JAMA. Published online May 07, 2020. doi:10.1001/jama.2020.1522
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