Living systems exhibit remarkable abilities to self-assemble, regenerate, and remodel complex shapes. How cellular networks construct and repair specific anatomical outcomes is an open question at the heart of the next-generation science of bioengineering. Developmental bioelectricity is an exciting emerging discipline that exploits endogenous bioelectric signaling among many cell types to regulate pattern formation. We provide a brief overview of this field, review recent data in which bioelectricity is used to control patterning in a range of model systems, and describe the molecular tools being used to probe the role of bioelectrics in the dynamic control of complex anatomy. We suggest that quantitative strategies recently developed to infer semantic content and information processing from ionic activity in the brain might provide important clues to cracking the bioelectric code. Gaining control of the mechanisms by which large-scale shape is regulated in vivo will drive transformative advances in bioengineering, regenerative medicine, and synthetic morphology, and could be used to therapeutically address birth defects, traumatic injury, and cancer.

374 Scaling and the design of miniaturized chemical-analysis systems D. Janasek, J. Franzke & A. Manz 381 Developing optofluidic technology through the fusion of microfluidics and optics D. Psaltis, S. R. Quake & C. Yang 387 Future lab-on-a-chip technologies for interrogating individual molecules H. Craighead 394 Control and detection of chemical reactions in microfluidic systems A. J. deMello

Cover illustrationEnzymes that contain metal atoms (yellow) at their active sites are involved in many biological processes. (Artwork by N. Spencer) METALLOPROTEINS Proteins can catalyse a remarkably wide range of chemical reactions. Yet the main differences among polypeptides are in the side chains of naturally occurring amino acids, which account for only a small proportion of the possible chemical functionality. The diversity of function is instead made possible partly because proteins can incorporate cofactors -such as small organic molecules, single metal atoms or clusters that contain metal and non-metal atoms -into their active sites.Almost half of all enzymes require the presence of a metal atom to function. These 'metalloproteins' have captivated chemists and biochemists, particularly since the 1950s, when the first X-ray crystal structure of a protein, sperm whale myoglobin, indicated the presence of an iron atom. Much is now understood about how metal clusters are assembled, how metal ions or clusters are introduced into target proteins, and which metal ions are commonly found in metalloenzymes. In addition, we are much closer to understanding the mechanisms by which metalloenzymes catalyse such a range of complex chemical reactions. But, despite more than half a century of research by chemists, biochemists and cell biologists, many discoveries remain to be made.The articles in this Insight highlight some of the most exciting current research on metalloproteins, including how enzymes containing complex metal clusters metabolize small gaseous molecules, how proteins containing iron-sulphur clusters are assembled, and how metalloenzymes containing a single metal ion catalyse the halogenation of small organic molecules.We are pleased to acknowledge the financial support of AstraZeneca in producing this Insight. As always, Nature carries sole responsibility for all editorial content and peer review. Joshua Finkelstein, Senior Editor REVIEWS814 Structure-function relationships of anaerobic gas-processing metalloenzymes

Regeneration is regulated not only by chemical signals but also by physical processes, such as bioelectric gradients. How these may change in the absence of the normal gravitational and geomagnetic fields is largely unknown. Planarian flatworms were moved to the International Space Station for 5 weeks, immediately after removing their heads and tails. A control group in spring water remained on Earth. No manipulation of the planaria occurred while they were in orbit, and space‐exposed worms were returned to our laboratory for analysis. One animal out of 15 regenerated into a double‐headed phenotype—normally an extremely rare event. Remarkably, amputating this double‐headed worm again, in plain water, resulted again in the double‐headed phenotype. Moreover, even when tested 20 months after return to Earth, the space‐exposed worms displayed significant quantitative differences in behavior and microbiome composition. These observations may have implications for human and animal space travelers, but could also elucidate how microgravity and hypomagnetic environments could be used to trigger desired morphological, neurological, physiological, and bacteriomic changes for various regenerative and bioengineering applications.

Small molecules that induce or stabilize the association of macromolecules have proven to be useful effectors of a wide variety of biological processes. To date, all examples of such chemical inducers of dimerization have involved known ligands to well-characterized proteins. The generality of this approach could be broadened by enabling the discovery of heterodimerizers that target known macromolecules having no established ligand, or heterodimerizers that produce a novel biologic response in screens having no predetermined macromolecular target. Toward this end, we report the construction of a diversified library of synthetic heterodimerizers consisting of an invariant ligand that targets the FK506-binding protein (AP1867) attached to 320 substituted tetrahydrooxazepines (THOXs). The THOX components were generated by a combination of liquid- and solid-phase procedures employing sequential Mitsonobu displacements to join two structurally diversified olefin-containing monomers, followed by ruthenium-mediated olefin metathesis to effect closure of the seven-membered ring. The 320 resin-bound THOX ligands were coupled in parallel to AP1867, and the products were released from the resin to yield candidate heterodimerizers in sufficient yield and purity to be used directly in biologic testing. A representative panel of 25 candidate heterodimerizers were tested for their ability to pass through the membrane of human fibrosarcoma cells, and all were found to possess activity in this tissue culture system. These studies pave the way for further studies aimed at using small-molecule inducers of heterodimerization to effect novel biological responses in intact cells.