CHE.496/2008/Schedule/Systems biology and synthetic biology

Systems biology and synthetic biology

• Discussion leader: George W.

• Systems biology as a foundation for genome-scale synthetic biology link
  • This article discusses the connection between systems biology and synthetic biology, specifically how modern advances in systems biology aid the development of the nascent field of synthetic biology
  • One current approach taken by systems biologists is to 'reconstruct' a system
    • This is done by first incorporating every relevant reaction into a stoichiometric matrix
    • From this, a set of parameters can be identified
    • By applying 'flux balance analysis' to this model, a concrete model that accurately predicts temporal evolution of the system can be achieved
    • Requires many parameters to be defined as well as a 'demand reaction' to drive the system, which is unknown in most cases outside of exponential growth
  • Much of the software developed for systems biology will be useful in the pursuit of computational analysis in synthetic biology
  • In order to deal with unknown parameters, synthetic biologists can use directed evolution to make a system conform to known parameters; in short, make the system imitate the model
  • New experimental techniques are always improving parameter estimation and system reconstruction, and these will clearly benefit both systems and synthetic biologists
  • Maybe we can use some of these techniques in our own work?
    • Developing our own 'reconstruction' seems unlikely to be feasible, although if we're working with a known system, we may be able to use others' results
    • The OptStrain strategy may be feasible if we do metabolic engineering, but I doubt we'll be doing a qualitatively new pathway, so this is likely unnecessary

• Modular approaches to expanding the functions of living matter link
  • This article describes many techniques used by modern synthetic biologists to achieve novel function in biological systems
  • The first section describes how we can take advantage of machinery already present in the cell to engineer qualitatively different function from anything naturally occurring
    • Elowitz' repressilator shows oscillation from mutual repression, a system never observed in nature
      • This system is extremely sensitive to noise, so is difficult to accurately model except on a gross population level
    • Collins' bistable switch permits epigenetic memory, allowing novel response to various stimuli
    • Leibler's work systematized topological consequences of several repressors and promoters
      • By analyzing 512 different topologies, many useful logical functions were derived
    • V. fischeri's quorum sensing permits tumor infiltration, and the familiar bullseye spatial differentiation can be achieved by separation into two functional halves, signal sending and receiving
  • The second section explores various unnatural machinery introduced to the cell
    • Voigt et. al. were able to create a bacterial camera by incorporating an engineered photoreceptor
    • Goulian et. al. modified chemotaxis receptors in E. coli to respond to a variety of attractors
    • Hellinga's dead-end eliminaton algorithm permits creation of proteins that recognize novel substrates, such as TNT and serotonin
    • Lim et. al. combined two scaffold proteins to link the input of one to the output of the other, a connection completely absent in the natural system
    • Schultz has been able to expand the genetic code, potentially providing radically different protein structures and functions from anything in nature
  • Perhaps one of the more interesting ideas present in the article is that of post-transcriptional regulation, as this provides tools independent of genetic manipulation to control and regulate
    • Smolke's caffeine sensor uses RNA aptamers to suppress target mRNA from transcription in the presence/absence of a specific ligand (in this case, caffeine)
      • Not only does this give extremely rapid suppression of the target mRNA, but it also provides orthogonal suppression of any number of targets, as the aptamers can be finely-tuned for a wide range of inducers/suppressors
    • Collins et. al. have been able to repress RBSs with specific sequences directly before them designed to form a hairpin with the RBS; only when RNA that binds the suppressor sequence is present is the RBS free to bind to the ribosome
    • Rackham and Chin have created functionally new ribosomes that do not interact with the original genome at all
      • These can bind to new RBSs that won't interfere with the original ribosomes
      • Orthogonal ribosomes can be used to create logical circuits
  • There was no dearth of examples in this article, all of which are important to be aware of, and some of which might be useful in our own project
    • Orthogonal function seems paramount in development of large-scale complex systems, since unpredicted interaction between disparate parts will swiftly render them at best impaired, at worst non-functional
    • Combinations of pre- and post- transcriptional regulation allow control of the system on multiple timescales
• George Washington 16:29, 2 April 2008 (EDT)