Perspective: Systems Biology Can Provide Guidance to Synthetic Biology in the Pursuit of New Drug Targets

Eberhard Otto Voit^*

• The University of Texas at Dallas, Richardson, United States

Many diseases are caused by an elevated or decreased level of some metabolite but it is not always a priory clear which process or processes associated with the metabolite could or should be altered pharmaceutically to effect a return to normalcy. With a case study, this perspective demonstrates the power of systems biological analysis for guiding drug targeting. The case study analyzes a seemingly simple linear metabolic pathway whose end product triggers the activation of a transcription factor that controls the gene coding for an enzyme catalyzing an upstream step within the pathway. This physiological feedback mechanism might seem artificial but constitutes a type of circuit observed in physiology and pathology. For example, the illustration pathway is a simplified version of a cancer-related redox circuit involving the enzyme NQO1 (NAD(P)H:quinone oxidoreductase 1), which is protective against oxidative stress. The circuit can be pharmaceutically manipulated with the anti-cancer agent β-lapachone, which induces apoptosis through the generation of reactive oxygen species and thereby inhibits tumor growth. The catalysis of β-lapachone by NQO1 results in the generation of hydrogen peroxide, which activates a transcription factor controlling the synthesis of NQO1, thereby closing a positive feedback loop. The analysis of a simplified version of this scenario demonstrates how a physiological circuit can lead our intuition astray. Dynamic modeling easily overcomes this challenge and thereby offers a powerful exploratory tool for the targeted design of pharmaceutical interventions. It permits reliable explanations and prescriptions for feasible solutions that might be implemented with methods of synthetic biology.