Design and Synthesis of Molecular Networks

Elisa Franco, Ph.D.
California Institute of Technology
Department of Control and Dynamical Systems

How do living organisms process information and implement their responses to external stimuli?  Even  in  the  simplest  cells,  sensing,  computation  and  actuation  are  structurally embedded  in  the  biochemistry  of  complex  molecular  networks,  which  we  often  fail  to  systematically  explain.  Quoting  Richard  Feynman,  what  we  cannot  create,  we  do  not  understand:  by  building  simple  molecular  networks  from  the  bottom-up,  in  a  controlled environment,  we  have  an  opportunity  to  gain  insight  into  the  design  principles  of  their more  complicated,  naturally  occurring  counterparts.    In  this  talk  I  will  describe  the design, modeling and synthesis of in vitro molecular circuits using simple building blocks: DNA,   RNA   and   proteins.   In   particular,   I   will   present   my   research   on   two   specific challenges:  flow  regulation  and  scalability  of  biochemical  networks.  Cellular  pathways rely  heavily  on  a  regulated  flow  of  nucleic  acids,  enzymes  and  other  metabolites.  I  will demonstrate  how  negative  feedback  can  be  used  to  coordinate  and  match  the  activity  of two synthetic genes, minimizing waste of chemical reagents. The proposed architecture is robust with respect to initial conditions and specific uncertain parameters. Scaling up our perspective  to  the  coordination  of  a  large  number  of  molecular  circuits,  biochemical oscillators promise to have a role analogous to digital clocks, which can drive millions of transistors.  As  a  starting  point,  we  have  used  a  tunable  biosynthetic  oscillator  to  drive conformational   changes   of   a   DNA   nano-mechanical   device   called   "DNA   tweezers". However,  due  to  the  imperfect  modularity  of  the  system,  the  operating  point  of  the oscillator   is   remarkably   deteriorated   by   high   concentrations   of   its   "load".   This  retroactivity effect is well known in engineered systems, and classical examples are given by  voltage  drops  in  power  grids  or  pressure  losses  in  pipe  networks.  This  undesired back-action  was  reduced  by  engineering  an  "insulator  circuit",  the  molecular  equivalent of an  operational amplifier, which improved the modularity and scalability of the system.

Elisa  Franco  is  currently  a  graduate  student  at  the  California  Institute  of  Technology,  in the  department  of  Control  and  Dynamical  Systems.  She  received  her  Laurea  degree  in Power Systems Engineering from the University of Trieste, Italy, where she also earned a PhD in Automatic Control. Her current research interests are in the field of synthetic and systems biology.