Commentary

Centrioles are among the most beautiful of biological structures. How their highly conserved nine-fold symmetry is generated is a question that has intrigued cell biologists for decades. Two recent structural studies provide the tantalizing suggestion that the self-organizing properties of the SAS-6 protein hold the answer.

The GTPase switch is a versatile molecular device used by many proteins, such as the small GTPases, to regulate an astounding number of functions. Although the basics of the guanine nucleotide cycle are now well established, the next challenge is to reach an integrated view of how these proteins use it to orchestrate signaling pathways.

Sensors and reporters are among the most exciting tools used in cell biology. Now, they are increasingly used in developmental biology and medicine because they allow us to spy on events in living cells and organisms, including humans, in real time and with high spatial resolution. Herein, we discuss multiple design options for fluorescent sensors and reporters as well as strategies to improve their properties and increase development.

Lambda's 'genetic switch' responds in a dramatic all-or-none fashion to an environmental signal, activating transcription of certain genes as it turns off others. The switch illustrates principal features of many biological regulatory processes.

In response to decreasing Ca²⁺ levels in the endoplasmic reticulum, STIM proteins couple with Orai channels in the plasma membrane, leading to Ca²⁺ influx into the cell. In addition to Ca²⁺-related endoplasmic reticulum stress, STIM proteins are emerging as general stress sensors that react to multiple stress signals to orchestrate Ca²⁺ signaling and homeostasis.

This Commentary clarifies the meaning of the funnel diagram, which has been widely cited in papers on protein folding. To aid in the analysis of the funnel diagram, this Commentary reviews historical approaches to understanding the mechanism of protein folding. The primary role of free energy in protein folding is discussed, and it is pointed out that the decrease in the configurational entropy as the native state is approached hinders folding, rather than guiding it. Diagrams are introduced that provide a less ambiguous representation of the factors governing the protein folding reaction than the funnel diagram.

A new type of big science is emerging that involves knowledge integration and collaboration among small sciences. Because open collaboration involves participants with diverse motivations and interests, social dynamics have a critical role in making the project successful. Thus, proper 'social engineering' will have greater role in scientific project planning and management in the future.

Because of the complexity of biological systems, cutting-edge machine-learning methods will be critical for future drug development. In particular, machine-vision methods to extract detailed information from imaging assays and active-learning methods to guide experimentation will be required to overcome the dimensionality problem in drug development.

As biochemistry ventures out from its reductionist roots, concentration effects and high surface-to-volume ratios will challenge our current understanding of biological systems, with colloidal and surface chemistry leading to new insights and approaches. How must our thinking change, what new tools will we need and how will these new tools be developed?

The pharmaceutical industry is in a period of crisis due to the low number of new drug approvals relative to the high levels of R&D investment. It is argued here that improving the quality of target selection is the single most important factor to transform industry productivity and bring innovative new medicines to patients.

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.