Commentary in 2008

Chemical biology and systems biology have grown and evolved in parallel during the past decade, but the mindsets of the two disciplines remain quite different. As the inevitable intersections between the disciplines become more frequent, chemical biology has an opportunity to assimilate the most powerful ideas from systems biology. Can the integrationist mindset of systems biology liberate chemical biology from the compulsion to reduce everything to individual small molecule–target pairings?

As the field of chemical biology matures, its practitioners are tackling ever more sophisticated biological problems. Chemical approaches, both synthetic and analytical, provide researchers with powerful new technologies to perturb, dissect and even reconstruct complex biological systems. Here we discuss the special challenges and opportunities confronted at the burgeoning interface of chemical and systems biology.

Although much is known about the molecular components of cellular signaling pathways, very little is known about how these multicomponent biochemical machineries process complex extracellular signals to generate a consolidated cellular response. A newly developed theoretical approach for reverse engineering network structure—analyzing how perturbations propagate in a network—can be combined with chemical perturbations and quantitative detection approaches to reveal the causal connections within protein networks in cells. This information indicates the dynamic capabilities of a network and thereby its potential function.

Undergraduate research experiences help retain students in science majors and prepare our workforce for increasingly competitive jobs. Course-based approaches to research and inquiry allow educators to reach larger numbers of students and provide an entry into further research experiences.

Chemical biology continues to grow and blur the theoretical and empirical boundaries between chemistry and biology. Federal funding agencies, including the US National Science Foundation, will be essential to support the development of interdisciplinary research fields.

Funding support for chemical biology is essential for its growth around the world. A new funding initiative from the National Natural Science Foundation of China provides a model of a targeted funding program in the area of signal transduction.

An emerging generation of scientists trained at the interface of chemistry and biology is providing new tools and insights into the workings of biological systems. Private foundations represent an important funding option for scientists at this interface.

Cooperative binding effects pervade biology. Only a few basic principles are at play, but in different biological contexts cooperativity appears in distinct guises to achieve different ends. Here I discuss some of the manifestations of cooperativity that are most important in biology and drug discovery as they pertain to systems at different levels of complexity and also highlight aspects of this broadly important phenomenon that remain poorly understood.

The development of single-molecule tools has significantly impacted the way we think about biochemical processes. Watching a single protein in action allows us to observe kinetic details and rare subpopulations that are hidden in ensemble-averaging techniques. I will discuss here the pros and cons of the single-molecule approach in studying ligand binding in macromolecular systems and how these techniques can be applied to characterize the behavior of large multicomponent biochemical systems.

For the last 30 years, the production of affinity reagents and particularly antibodies for research and therapeutic applications has been dominated by hybridoma and polyclonal technologies, while more modern, reliable and inexpensive approaches have lagged. Here we discuss why this is the case and how a cultural shift in the biomedical research community could bring the new technologies for creating antibodies and other tailor-designed binding proteins into the mainstream, with the potential for myriad new applications in research and medicine.

Many macromolecular complexes function as nanoscale machines performing important cellular jobs. However, their complex and dynamic natures pose challenges for detailed structure-function analysis. Small-molecule inhibitors, which can be identified by high-throughput screening, provide important leverage into the study of macromolecular assemblies by allowing researchers to capture transient intermediate states and probe important functional components.