Dynamics of Molecular Networks for the Next Generation of Drug Development and Personalized Medicine

The great challenge for contemporary biomedicine is to translate detailed knowledge about the molecular components of living systems into a useful understanding of control over the fully assembled, complex organisms. This is particularly critical in the context of chronic diseases.  Development of new medicines, personalization of clinical therapeutics and prevention of common diseases would all be radically transformed if markers were available that quantified the activity of the major biologic pathways that drive disease pathogenesis. 

The goal is viable assays of disease-modifying processes:  causal pathways that predict pathologic and clinical outcomes.

I will describe new techniques for measuring flux through such pathways in vivo, involving stable isotope metabolic labeling and mass spectrometric analyses of perturbed isotope ratios.  Emphasis will be on new technologies that we have developed – in particular, Proteome Dynamics, “virtual biopsies” (of processes in inaccessible tissues in humans) and metabolic flux microscopy (kinetic imaging).  These approaches all use tandem mass spectrometry combined with in vivo labeling, often with heavy water. 

The key features of these biomarker platforms are predictivity and interpretability, both deriving from their intrinsic functional significance, and translatability into humans.  Applications in fibrogenic disorders, cancer, neurodegenerative conditions, sarcopenia/muscle wasting, and diabetes will be presented.