Scientific Retreats 2007

August 5, 2007 (historical)

Systems Biology of Inflammation

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases is to "support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases." Because some of the diseases affecting the musculoskeletal system and skin have harmful inflammatory response components, there is a need to develop an understanding of inflammation in order to better diagnose, treat, predict, and/or prevent them. However, most are complex, multifactorial polygenic diseases, such that the important etiologic and mechanistic questions are difficult to answer. The complex, dynamic behavior of the immune system and its wealth of intricate intra- and intercellular interactions make it ideal for the application of systems biology.

What is "systems biology?" It is the term applied to a comprehensive research strategy that enables the integration of many different types of information in order to better understand complex biological systems. One can broadly define a "system" as a group of independent but interconnected elements that function together to comprise a unified whole. The boundaries of the system may not be clearly defined or definable, especially if multicellular organisms are being investigated. Instead, one may start with an observable phenotype, for example, "systemic lupus erythematosus" or "psoriasis," and use a systems biology approach to identify subsets within the overall system that specifically relate to the emergence of that phenotype. The methodology of systems biology is an iterative process that begins with the identification of component parts and their respective interactions. The information is then integrated into a predictive (usually mathematical) model of system behavior, which is, in essence, a hypothesis that can be tested experimentally. The experimental results lead to the refinement of the model and, subsequently, new hypotheses.

The purpose of this session is to discuss the application of systems biology approaches to complex, inflammatory and autoimmune diseases.

Questions to be addressed during the discussion:

1. The identification of system parts and interactions can include gene expression, genetic variation, transcriptional regulation (protein-DNA interaction), RNA interference, and proteomics. The information is then integrated into a predictive model of behavior.

-What are some of the technologies being developed and utilized? What are critical characteristics of the assays in these types of studies?

-What are some of the databases available to the scientific community and how are they used?

-What are some of the confounding factors that complicate data interpretation?

2. Some key topics relevant to inflammation that can be addressed using a systems biology approach include the study of cytokine/chemokine networks, relevant signaling networks [for example, Toll-Like Receptor (TLR) and TLR-independent pathways of innate recognition], genetic or regulatory networks, and drug/treatment discovery.

-What are some of the complexities of the application of systems biology to these situations (and biological systems in general)?

-How do systems biology approaches help to differentiate between correlation and causation?

-What are the advantages of developing systems biology approaches to understanding complex disease?

-What scientific issues relevant to the biology and diseases in the NIAMS mission are ripe for exploration using systems biology approaches?

3. Systems biology approaches require the collaboration between scientists from multiple disciplines.

-This large interdisciplinary scientific approach is very expensive. What are some of the options available to provide support for NIAMS investigators for this type of research? Smaller partnerships/multi-project applications? NIH Roadmap? New Innovator Award Program?

-What are the strategies for getting diverse team members to work together, and how can NIH foster the development of the diverse teams that are needed for the application of systems biology approaches?

Background Materials

Aderem, A. Systems Biology: Its Practice and Challenges. Cell. 2005 May 20;121: 511-513.

Smith, KD, and H. Bolouri. Dissecting Innate Immune Responses with the Tools of Systems Biology. Current Opinion in Immunology. 2004, 17: 49-54.