Volume 4 Issue 11, November 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.

Multitargeted protein kinase inhibitors have shown great promise in cancer therapy, but the selectivity profiles of these compounds have largely relied on serendipity or 'off-target' activities rather than rational drug design. Purposefully designed compounds with activity against multiple target kinases bring us a step closer to personalized medicine.

Voltage-gated K⁺ channels assemble into complexes with Kvβs, a group of aldoketoreductases. The Kvβs regulate channel gating and localization, and voltage-dependent changes in the channel regulate AKR activity. Pan and colleagues now propose a new type of modulation of this complex. Cortisone disrupts the complex and relieves channel inactivation—which should reduce neuronal excitability.

The execution phase of cell death is driven by specific proteolytic signaling through cleavage of proteins by caspases. Within the mix of hundreds of newly identified caspase substrates lie the crucial proteolytic events whose sum defines the unique morphology known as apoptosis.

Bacteria produce and excrete toxic compounds classically categorized as waste products or chemical weapons. New work indicates a role for phenazines and SoxR, a transcription factor known for its role in defense against oxidative stress, in coordinating bacterial community growth.

The emergence of a primordial RNA world would have required the formation of RNA polymers of sufficient length to possess catalytic activities, which are difficult to obtain by spontaneous polymerization. An analysis of an autocatalytic assembly pathway that can self-construct a functioning ribozyme from smaller oligonucleotide building blocks describes a potential route for RNA extension.

Chemical biology and systems biology are beginning to intersect with increasing frequency, opening up opportunities for integrating new tools and concepts into both fields. In this issue, we highlight a number of exciting areas at the emerging interface of 'chemical systems biology'.