Commentary in 2010

The ability to alter cell identity with small molecules represents a powerful approach to restore biological function lost because of cellular deficiency. Developing this capability through advances in chemical biology could have an enormous impact on human health.

Post-transcriptional RNA modifications can be dynamic and might have functions beyond fine-tuning the structure and function of RNA. Understanding these RNA modification pathways and their functions may allow researchers to identify new layers of gene regulation at the RNA level.

Hyper-performing whole-cell catalysts are required for the renewable and sustainable production of petrochemical replacements. Chassis cells—self-replicating minimal machines that can be tailored for the production of specific chemicals—will provide the starting point for designing these hyper-performing 'turbo cells'.

Some of the most celebrated triumphs of chemical biology are molecularly targeted therapeutics to combat human disease. However, a grand challenge looms as informative diagnostic strategies must be developed to realize the full impact of these promising pharmaceutical agents.

In the postsequencing era, chemical biology is uniquely situated to investigate genomic DNA alterations arising through epigenetic modifications, genetic rearrangements or active mutation. These transformations significantly expand nature's diversity and may profoundly alter our view of DNA's coding potential.

Chemical biology is now able to discover molecules that manipulate virtually any biological target or process. It remains a grand challenge to leverage these molecules into useful probes that can be used to address unsolved problems in biology.

Rationally designing new strategies to control the human immune response stands as a key challenge for the scientific community. Chemical biologists have the opportunity to address specific issues in this area that have important implications for both basic science and clinical medicine.

The synthesis and biological annotation of small molecules from underexplored chemical space will play a central role in the development of drugs for challenging targets currently being identified in frontier areas of biological research such as human genetics.

Variations between single members of a bacterial population can lead to antibiotic resistance that is not gene based. The future of effective infectious disease management might depend on a better understanding of this phenomenon and the potential to manipulate both it and microbial population dynamics in general.

Engineering biosynthetic pathways to natural products is a challenging endeavor that promises to provide new therapeutics and tools to manipulate biology. Information-guided design strategies and tools could unlock the creativity of a wide spectrum of scientists and engineers by decoupling expertise from implementation.

The capability to generate multi-omic data sets raises the issue of resource allocation for data generation versus data curation and integration. The initial experience of researchers shows that the effort required for the latter can be much greater than that for the former.

Biological messiness relates to infidelity, heterogeneity, stochastic noise and variation—both genetic and phenotypic—at all levels, from single proteins to organisms. Messiness comes from the complexity and evolutionary history of biological systems and from the high cost of accuracy. For better or for worse, messiness is inherent to biology. It also provides the raw material for physiological and evolutionary adaptations to new challenges.

Excitatory synapses are located in confined chemical spaces called the dendritic spines. These are atypical femtoliter-order microdomains where the behavior of even single molecules may have important biological consequences. Powerful chemical biological techniques have now been developed to decipher the dynamic stability of the synapses and to further interrogate the complex properties of neuronal circuits.

Because of the large number of phospholipids, their highly active metabolism and our lack of understanding of protein-lipid specificity, lipid signaling is a particularly challenging subject to study. Help might come from new tools that will allow us to follow and manipulate lipids and lipid-binding proteins in living cells.

Bioactive lipid signaling allows individual cells within the body to 'see' the surrounding environment and to respond in ways that will benefit the whole organism. Successful drug development for bioactive lipid targets requires a deep knowledge of the biology and pathobiology of each specific lipid signaling pathway.

Artificial biosynthetic pathways are typically assembled and optimized progressively, from earlier to later steps. This commentary highlights the potential of an alternate regressive method for biochemical pathway design and generation, inspired by the retro-evolution hypothesis and the concept of retrosynthesis. In addition to being a pathway design tool, 'bioretrosynthesis' has potential as a construction and optimization methodology.

Chemical biologists frequently aim to create small-molecule probes that interact with a specific protein in vitro in order to explore the role of the protein in a broader biological context (cells or organisms), but a common understanding of what makes a high-quality probe is lacking. Here I propose a set of principles to guide probe qualification.

The complexity of cancer signaling and the resulting difficulties in target selection have strongly biased kinase drug discovery towards clinically validated targets. Recently, novel kinase targets that are uncharacterized have emerged from genome sequencing and RNAi studies. Chemical probes are urgently needed to functionally annotate these kinases and to stimulate new drug discovery efforts.

Bioactive compounds are most frequently identified via high-throughput screening campaigns. This article discusses the strengths and weaknesses of the most popular screening approaches and the utility of compounds derived from them.