Synthetic Biology Interdisciplinary Challenge 7
How do we move beyond genetics to engage chemical and physical approaches to synthetic biology?

Challenge Summary
The controlled manipulation of genetic information constitutes the “standard model” of synthetic biology.  But biological behavior is subject to control at many levels, and biological systems respond to a wide range of chemical and physical stimuli.  As cells and organisms adapt to their environments, they change the genes they express, the chemical substrates they use and the metabolites they produce.  They respond to changes in temperature, pH, and ionic strength, to light and mechanical forces, and to many other chemical and physical signals.  Researchers interested in creating new biological function can therefore draw on a set of tools that extends well beyond genetic manipulation.

Recent advances in chemistry, physics, and engineering have provided powerful new routes to novel biological behavior.  Chemists have demonstrated the capacity of cells and organisms to use non-standard substrates, including amino acids, fatty acids and sugars that don’t occur naturally.  Non-standard nucleotides can be processed with high fidelity by DNA polymerase, non-canonical amino acids are readily incorporated into natural and artificial proteins, and novel sugars and fatty acids have been used to probe post-translational modification on a proteome-wide scale.  Engineering of proteins and pathways has extended the diversity of substrates and products still further.

Physical tools such as patterning of cells on surfaces, microfabrication of three-dimensional cellular structures, and microfluidic delivery of proteins and other soluble factors also create significant opportunities for control of biological function.  Such tools will become increasingly important as synthetic biology embraces more fully the design of complex multicellular systems.

Key Questions

• What are the most promising approaches to chemical and physical control of biological function?  Inhibition or re-wiring of cellular pathways? Introduction of light-sensitive or mechanically-sensitive components?  Others?
• Which cellular pathways are most promising with respect to control by chemical and physical means? 
• What advantages might accrue from the development of novel chemical substrates (e.g., “abiological” nucleotides, amino acids, sugars, and other biosynthetic intermediates) for use in synthetic biology?
• Can we create organisms that prefer or even require altered sets of molecular substrates?  If so, what kinds of biological behavior might emerge from such adaptations?
• To what extent can we change the properties of biological macromolecules? Will such changes allow us to overcome some of the most important limitations of macromolecular therapeutics or industrial enzymes, e.g., sensitivity to proteases, surfactants, or dehydration?
• How can control of spatial relationships among cells contribute to the engineering of novel biological function? 
• Are there advances in bioreactor design and micro- and nano-fluidic technologies that should be brought to bear on problems in synthetic biology?