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STRATEGIES FOR FUTURE RESEARCH ON DISEASE MECHANISMS

The breakout group on disease mechanisms reviewed recommendations (#s1–7) relating to pathology, neuronal degeneration, genetic susceptibility, pathogens, immunopathogenesis, neuroimaging, and animal models. Dr. Robert Lisak, the group's rapporteur, relayed that the group decided not to prioritize this set of recommendations because all were deemed to be important and “absolutely intertwined.” As Dr. Jerry Wolinsky noted, “things shift so quickly in science . . . depending on where the data come from and how hot . . . it looks” that any prioritization made at the workshop might shift too soon to be useful. The group also pointed out that the report's recommendations for research on disease mechanisms were already underway.

The group agreed with the IOM report that priorities should balance scientific opportunity with organizational goals. Given the rapidly evolving nature of biomedical research, the real question posed by the group is whether funding agencies, such as NIH and the National MS Society, have adequate systems in place to monitor the latest research opportunities. The group proceeded to answer that question affirmatively—that funding agencies are using appropriate means to actively monitor research developments, and that they have the flexibility to take advantage of new trends. According to Dr. Wolinsky, one member of the group,

“When we decided not to prioritize, we also decided that we can feel comfortable doing that because ... the National MS Society, the NIAID, the NIH, and the NINDS were doing an adequate job of reviewing the landscape of science priorities and changing priorities and that we didn't see that there was an important need to change those structures or how they are functioning ... this is an important aspect on which there was consensus.”

The group also discussed whether any large-scale scientific initiatives were warranted to advance understanding of disease mechanisms. They regarded the ongoing international initiative, “The MS Lesion Project,” as fulfilling an important research question that a large-scale initiative should address—namely, whether there are distinct neuropathological subtypes of MS. This project, the largest ever supported by the National MS Society, integrates tissue samples and imaging in a longitudinal study design. The breakout group stressed the benefit of frequent monitoring of the project's progress and the importance of smaller-scale studies to confirm findings.

The breakout group emphasized that the report contained many other suggestions for promising areas of research not highlighted as formal recommendations, for example, tissue banks and gender. The breakout group also agreed that far more research emphasis was warranted on microglia, other antigen-presenting cells, and endothelial cells, as well as on the interactions between all cell types involved in MS pathogenesis. Further, the group proposed that the Committee's recommendation (#3) to study genetic susceptibility in MS be expanded to incorporate the role of genes



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Page 4 STRATEGIES FOR FUTURE RESEARCH ON DISEASE MECHANISMS The breakout group on disease mechanisms reviewed recommendations (#s1–7) relating to pathology, neuronal degeneration, genetic susceptibility, pathogens, immunopathogenesis, neuroimaging, and animal models. Dr. Robert Lisak, the group's rapporteur, relayed that the group decided not to prioritize this set of recommendations because all were deemed to be important and “absolutely intertwined.” As Dr. Jerry Wolinsky noted, “things shift so quickly in science . . . depending on where the data come from and how hot . . . it looks” that any prioritization made at the workshop might shift too soon to be useful. The group also pointed out that the report's recommendations for research on disease mechanisms were already underway. The group agreed with the IOM report that priorities should balance scientific opportunity with organizational goals. Given the rapidly evolving nature of biomedical research, the real question posed by the group is whether funding agencies, such as NIH and the National MS Society, have adequate systems in place to monitor the latest research opportunities. The group proceeded to answer that question affirmatively—that funding agencies are using appropriate means to actively monitor research developments, and that they have the flexibility to take advantage of new trends. According to Dr. Wolinsky, one member of the group, “When we decided not to prioritize, we also decided that we can feel comfortable doing that because ... the National MS Society, the NIAID, the NIH, and the NINDS were doing an adequate job of reviewing the landscape of science priorities and changing priorities and that we didn't see that there was an important need to change those structures or how they are functioning ... this is an important aspect on which there was consensus.” The group also discussed whether any large-scale scientific initiatives were warranted to advance understanding of disease mechanisms. They regarded the ongoing international initiative, “The MS Lesion Project,” as fulfilling an important research question that a large-scale initiative should address—namely, whether there are distinct neuropathological subtypes of MS. This project, the largest ever supported by the National MS Society, integrates tissue samples and imaging in a longitudinal study design. The breakout group stressed the benefit of frequent monitoring of the project's progress and the importance of smaller-scale studies to confirm findings. The breakout group emphasized that the report contained many other suggestions for promising areas of research not highlighted as formal recommendations, for example, tissue banks and gender. The breakout group also agreed that far more research emphasis was warranted on microglia, other antigen-presenting cells, and endothelial cells, as well as on the interactions between all cell types involved in MS pathogenesis. Further, the group proposed that the Committee's recommendation (#3) to study genetic susceptibility in MS be expanded to incorporate the role of genes

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Page 5in disease heterogeneity, clinical course, and response to drug therapy. The group did not agree as to whether there are leading genetic “hot spots” to pursue more vigorously. In studying the role of pathogens in MS, Dr. Lisak reported that the group felt that research on pathogens should not focus on a “single causative agent,” but on the multifarious roles of infectious agents in “possible initial triggers, and ... in relapses, and secondary damage.” The group also emphasized the importance of studying interactions between pathogens and the immune system, as well as studying the possibility of distinct pathogens being involved to varying degrees in different patients. In the previous day's discussion of pathogens, Committee member Dr. Raymond Roos explained that the Committee had recommended pathogen research because “whether MS is an inflammatory disease because a pathogen is involved, or whether it is an inflammatory disease for another reason is an open question.” He also pointed to the existence of “wonderful tools that haven't really been exploited” for identifying pathogens in MS. Reflecting his skepticism, Dr. Kees Lucas retorted, “Having a wonderful rod is not a reason to go fishing.” Thus although the group reported that they agreed in general that it was unwise to prioritize recommendations #s1–7, at least one participant felt that recommendation #4 was less important than the others. The breakout group highlighted investment in animal models. “We thought it was important to reaffirm that animal models are important ... and that different animals and different models are important ...,” said Dr. Lisak. The group agreed that many types of animal models are needed, as was animal imaging, to study distinct aspects of pathogenesis. The group did not reach consensus about whether there was a need for a central facility for studying nonhuman primate models. They acknowledged the significance of primate models in current research, but did not agree on the need for extra investment in a central facility. The ensuing discussion focused on the value of a central primate facility. Dr. Reingold of the National MS Society indicated that the Society and NIH had co-funded a central facility for many years, yet eventually abandoned it. Several participants noted the advantages of such a facility: primates' close biological fidelity to humans, their utility for uncovering medication safety problems prior to human clinical trials, and their role in teasing apart disease pathogenesis. The disadvantage is that a primate facility requires large, long-term investment that may not be fruitful. Another discussion centered on the value of supporting a large-scale initiative to screen mouse mutants for abnormalities that resemble MS. Screening would be followed by intensive efforts to identify which genes are mutated, what their function is, and how they contribute to the observed abnormality. Some participants suggested that an initiative for MS could be conducted as part of a wider initiative to screen mouse mutants for many neurological diseases simultaneously. Others cautioned that with models of other diseases, intensive, years-long investigation of mutant mice had been unsuccessful because the model did not sufficiently resemble the human disease.