A systems biology approach to infectious disease research: innovating the pathogen-host research paradigm

Abstract

The twentieth century was marked by extraordinary advances in our understanding of microbes and infectious disease, but pandemics remain, food and waterborne illnesses are frequent, multidrug-resistant microbes are on the rise, and the needed drugs and vaccines have not been developed. The scientific approaches of the past-including the intense focus on individual genes and proteins typical of molecular biology-have not been sufficient to address these challenges. The first decade of the twenty-first century has seen remarkable innovations in technology and computational methods. These new tools provide nearly comprehensive views of complex biological systems and can provide a correspondingly deeper understanding of pathogen-host interactions. To take full advantage of these innovations, the National Institute of Allergy and Infectious Diseases recently initiated the Systems Biology Program for Infectious Disease Research. As participants of the Systems Biology Program, we think that the time is at hand to redefine the pathogen-host research paradigm.

FIG 1

Common and distinct elements of the four NIAID Systems Biology Centers. The National Institute of Allergy and Infectious Diseases (NIAID) sponsors the Systems Biology Program for Infectious Disease Research. Each of the four centers focuses on unique aspects of the host-pathogen response while using several common approaches and techniques (center circle).

FIG 2

Iterative cycles of perturbation biology. The infectious disease questions, the first step in the cycle, determine the appropriate biological models and technologies utilized to generate multidimensional data. Data analysis and integration identify key components, pathways, and networks which allow for the construction of a predictive model. Model-predicted biological bottlenecks or key network nodes are validated by performing additional targeted experiments and data integration, resulting in a refined model. Importantly, several rounds of biological perturbations (i.e., use of mutant pathogens, cellular small interfering RNA [siRNA] knockdowns or knockout mice) are required to produce a predictive model that could be effectively utilized by the general infectious disease community. In addition to a more comprehensive understanding of the host-pathogen response and testable models, this type of perturbation biology will produce publicly disseminated multidimensional data sets and potentially both diagnostic signatures and drug targets.