We, and others, have limited evidence that OCBs can persist in the CSF even after chronic treatment with RTX, indicating that inepte humoral immune responses have not been eliminated from the CNS. shift in understanding how the inflammatory phase of MS develops, and will hopefully lead to development of increasingly selective therapies against culprit B cells and related humoral immune system pathways. More broadly, these studies illustrate how lessons learned from the bedside have unique power to inform translational research. They highlight the essential role of clinician scientists, currently endangered, who navigate the rocky and often unpredictable terrain between the worlds of clinical medicine and biomedical research. Keywords: Multiple sclerosis, Charcot Lecture == Introduction == Those of us engaged in biomedical research understand well the sluggish pace of discovery, the disappointments, and the myriad constraints that complicate our lives. For scientists who are also clinicians, the joys of clinical medicine are an ever-present draw and a pull away from the laboratory; rewards of clinical work are reliable, providing the opportunity to help 10 or maybe 20 patients in a busy day, to experience a series of professional successes before retiring each night, and to be spared the disappointment of Naproxen etemesil rejected manuscripts, unfunded grants, or most crushingly when months or even years of work lead to less than expected progress. These downsides of a career in research are overwhelmed, however , by the thrill of learning something that has never been known before, and especially by the joy of making a medically useful discovery, something that happens, if one is fortunate, perhaps a few times over the course of a career. For those of us involved in the B cell story in multiple sclerosis (MS), such a happening occurred on a crisp Friday afternoon in northern California; it was September 2006, and the event was the unblinding of the phase II anti-CD20 rituximab (RTX) study (Figure 1). 1Looking back, the joy was twofold. First, Naproxen etemesil we saw evidence of a potentially powerful new approach for therapy of relapsing MS. Second, despite this success, it was also evident that our scientific rationale behind the clinical testing of RTX for MS NOP27 was almost certainly incorrect. Looking back, this was the best possible result of a translational research experiment. We identified a novel approach that appeared to offer Naproxen etemesil significant benefit for patients, and yet the data also sent us back to the laboratory in new and unexpected research directions. Indeed, the rubber meets the road when ideas born in the laboratory are formally road-tested at the bedside, and when data from real-life patients send us back to the laboratory armed with new hypotheses. Translational medicine is most effective when information flow is bidirectional, linking the laboratory with the clinic. == Figure 1 . == The phase IIB trial of RTX in relapsing MS. Patients were treated on day 0 and again on day 15 with either 1000 mg intravenous RTX or placebo. In the figure, the mean number of gadolinium (Gd)-enhancing lesions is shown by week for the RTX (blue) and placebo (black) groups. The primary endpoint was the total composite number of Naproxen etemesil enhancing lesions detected at weeks 12, 16, 20, and 24. There was a 91% relative reduction in new enhancing lesions in the RTX group. Adapted from Hauser et al. 1RTX: rituximab; MS: multiple sclerosis. == The early days == An early experience occurred in the late 1970s during my neurology residency. A number of us were sitting around a conference room on the ninth floor of the old Vincent Burnham building at Massachusetts General Hospital with our chair of neurology, Raymond D. Adams. A postdoctoral fellow from Massachusetts Institute of Technology (MIT) was presenting some work in experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP). Adams noted, with a touch of sarcasm, that the Naproxen etemesil paralysis observed in the rodents likely resulted from peripheral nerve, and never central nervous system (CNS), disease. Indeed, he emphasized that the pathology of EAE and MS.