The Puzzle of Complex Disease: The Signaling Piece

Humans are complicated biological systems with a natural tendency to try to maintain a healthy and "normal" physiological state. A diseased condition can arise from a multitude of perturbations of this homeostatic scenario. These perturbations can be the result of genetic, environmental, or behavioral factors, or a combination of these. Discussed in this week's issue of Science The Puzzle of Complex Diseases ( ) is the tremendous challenge to understanding how complex "multifactorial" diseases, such as heart disease, diabetes, and cancer, evolve and how they can be effectively treated. How do clinical advances occur and where does signal transduction knowledge fit in? According to the Science Viewpoint by Rees ( ), there is no simple correspondence between genotype and phenotype in a complex disease situation. Observing patient responses to treatments and paying attention to potential side effects of treatments can even provide unexpected insights into the progression of other complex diseases. For example, retinoids, now widely used to treat skin disorders, were initially used in the clinic for a different application. Whereas the clinic provides the opportunity to observe patient responses to therapeutic interventions and discover physiological connections, bench research can provide comprehensive information on genes, proteins, and signaling networks relevant to disease pathology. This mechanistic insight into complex disease development can lead to strategies for the design of specific drugs. In a STKE Perspective, Liebman ( ) explains an approach that integrates both clinical data with experimental findings, and the challenges to such an attempt. Many examples now exist where the underlying genetic defects for a disorder or cellular regulatory processes affected during disease progression have been uncovered. One example described by Courtois and Israel ( ) in a Perspective from the STKE Archive is the nature of the epidermal disorder called incontinentia pigmenti, which has been gleaned from understanding the regulation of the transcription factor NF-κB. Other examples where understanding the cellular signaling network may assist in therapeutic intervention are the hypermetabolic disease cachexia, and type II diabetes. In the STKE Perspective, Tracey ( ) describes a number of signaling molecules (including tumor necrosis factor and interferon gamma) that are implicated in cachexia and that may be a guide to future therapeutic strategies. In the STKE Archive, a Perspective by Rangwala and Lazar ( ) describes new therapuetic agents that affect the nuclear hormone receptor peroxisome proliferator-activated receptor γ, which is the target for anitdiabetic drugs used to treat type II diabetes. In a Science Viewpoint, Strohman ( ) discusses how the application of a systems approach to understanding biological processes, such as metabolism, may aid in making useful predictions about complex diseases. Systems approaches to cellular signaling networks on a more basic level is the topic of the Perspectives by Lok ( ) and Ashman et al . ( ) in the STKE Archive. Complex diseases include psychiatric disorders, heart disease, and cancer. The descriptive profile of the psychiatric disorder schizophrenia now includes signaling through the N -methyl-D-aspartate (NMDA)-subtype of glutamate receptors, described in the Review by Sawa and Snyder ( ) in Science . This complex disease puzzle may also include modulators of NMDA receptors, such as the neurosteroids described by Gibbs and Farb ( ) and by Tasker ( ) in Perspectives available in the STKE archive. The complexities of some heart conditions are now beginning to be understood at cellular and molecular levels. A Perspective by Fozzard and Kyle ( ) describes how alteration of ion channel glycosylation underlies abnormalities characteristic of cardiac arrhythmias, and a Review in the STKE archive by Xiao ( ) describes the role of β-adrenergic receptor signaling in chronic heart failure. Cancer presents one of the most complex disease progressions from initial cellular transformation to metastasis and colonization of new tumor sites. A Protocol by Dong and Cmarik ( ) describes how cells can be isolated for analysis to study the molecular and biochemical events associated with cellular transformation. In the STKE archive, the Review by Mastumoto and Claesson-Welch ( ) describes the molecular pathways leading to angiogenesis, the inhibition of which is a major avenue being pursued for cancer treatments. No single discipline or approach alone will likely solve the puzzle of complex diseases. Insights into signaling mechanisms have surely provided many essential pieces and, hopefully, will help in the synthesis of more effective diagnoses and treatments in the future. Featured in This Focus Issue on The Puzzle of Complex Diseases Related Resources at STKE