Bifurcation of Diseases

Featured Faculty

Professor Guanyu Wang


Dr. Wang considers biological problems from different perspectives: evolutionary time scale, organismal level, and of course, the molecular level. Recent interests include biomolecular networks and synthetic biology; Singularity analysis of complex diseases that reveals their mechanistic connections and their evolutionary underpinning.

Our lives are threatened by complex diseases many of which are untreatable. What make things even worse are the triplet epidemics (cancer, obesity, and diabetes) which are escalating at the same time and in our time.  In the US, about 2/3 of the population is overweight; about 1/3 children born after year 2000 would develop diabetes; about 1/3 women and 1/2 men would develop cancer during their lifetime. These threats urge novel concepts and theories, fostered by profound physical thinking, to touch the nature of these diseases.  

     The concurrency implies that deep connections may exist and underlie these diseases. Therefore, a holistic perspective, from which these diseases are considered as qualitatively different but interconnected entities, is needed to identify the connections between these diseases and to revolutionize their treatments. A touchstone for this philosophy is the study on the PI3K-AKT-mTOR pathway, an evolutionarily conserved biomolecular network that controls energy metabolism and cell growth. By applying mathematical analysis, the dynamical behaviors constrained by the network have been identified and been mapped onto a phase diagram, which include: (1) A toggle switch (between activation and deactivation) that characterizes the normal response of the pathway to insulin or other growth factors ; (2) An irreversible switch that manifests as the constitutive activation of an oncoprotein and thus carcinogenesis; (3) The vanishing or delayed switch characteristics that underlie insulin resistance and thus diabetes. The revealed mechanistic connections may lead to novel strategies of therapeutic intervention by targeting the control mechanisms of the pathway, instead of single molecule targeted therapy. 

   The epidemics’ modern settings urged us to re-consider these diseases from an evolutionary optimization perspective. Indeed, modeling of the whole-body glucose-insulin homeostasis revealed that bistability (toggle switch behavior) is the optimal solution to a dilemma in glucose homeostasis: high insulin efficiency is required to confer rapidness in plasma glucose clearance, whereas an insulin sparing state is required to guarantee the brain’s safety during fasting. However, modern life styles (overnutrition and physical inactivity) may represent acute environmental changes that reduce the evolved optimality and cause maladaptation.  

     This project may be a good starting point for understanding related phenomena such as glucose addiction and the Warburg effect; and may provide valuable insights into diseases’ early detection and treatment. Future directions include cell culture or single cell experiments to verify theoretical predictions; application to synthetic biology; and MD simulation for drug discovery and optimization. 

© Webmaster 2013 @ Physics Department at GW