Method for the evolutionary design of biochemical reaction networks

Abstract

The present invention relates to methods for achieving an optimal function of a biochemical reaction network. The methods can be performed in silico using a reconstruction of a biochemical reaction network of a cell and iterative optimization procedures. The methods can further include laboratory culturing steps to confirm and possibly expand the determinations made using the in silico methods, and to produce a cultured cell, or population of cells, with optimal functions. The current invention includes computer systems and computer products including computer-readable program code for performing the in silico steps of the invention.

1 . A method for optimizing a function of a biochemical reaction network in a cell comprising:
 (a) calculating optimal properties of a biochemical reaction network by applying a computational optimization method to a list of reactions representing said biochemical reaction network;   (b) altering one or more reactions in said list of reactions in the biochemical reaction network and re-computing the optimal properties;   (c) repeating (b) until an optimized function is reached;   (d) constructing the genetic makeup of a cell to contain the biochemical reactions which result from (c);   (e) placing the cells constructed under (d) in culture under a specified environment, and   (f) cultivating the cells as in step (e) for a sufficient period of time and under conditions to allow the cells to evolve to the optimized function determined under (c), wherein the biochemical reaction network comprises a comprehensive biochemical reaction network.   
     
     
         2 . The method of  claim 1 , wherein the biochemical network is a metabolic network. 
     
     
         3 . The method of  claim 1 , wherein the biochemical network is a regulatory network. 
     
     
         4 . The method of  claim 2 , wherein the cells are prokaryotic cells. 
     
     
         5 . The method of  claim 2 , wherein the cells are eukaryotic cells. 
     
     
         6 . The method of  claim 1 , wherein the eukaryotic cells are yeast, fungal cells, animal cells or cell lines. 
     
     
         7 . The method of  claim 1 , wherein step (d) comprises altering one or more genes in the eukaryotic cell. 
     
     
         8 . The method of  claim 7 , wherein altering comprises introduction of a gene or genes into the eukaryotic cell. 
     
     
         9 . The method of  claim 7 , wherein altering comprises modification of an endogenous gene or genes in the eukaryotic cell. 
     
     
         10 . The method of  claim 1 , wherein the biochemical reaction network comprises a substantially whole biochemical reaction network. 
     
     
         11 . A method for optimizing production of a biochemical, comprising:
 (a) calculating optimal properties of a biochemical reaction network for production of a biochemical by applying a computational optimization method to a list of reactions representing said biochemical reaction network;   (b) altering one or more reactions in said list of reactions in the biochemical reaction network and re-computing the optimal properties;   (c) repeating (b) until an optimized function for production of said biochemical is reached;   (d) constructing the genetic makeup of a eukaryotic cell to contain the biochemical reactions which result from (c);   (e) placing the cells constructed under (d) in culture under a specified environment, and   (f) cultivating the cells as in step (e) for a sufficient period of time and under conditions to allow the cells to evolve to the optimized function determined under (c), wherein said cells produce said desired biochemical.   
     
     
         12 . The method of  claim 11 , wherein the biochemical network is a metabolic network. 
     
     
         13 . The method of  claim 11 , wherein the biochemical network is a regulatory network. 
     
     
         14 . The method of  claim 12 , wherein the cells are prokaryotic cells. 
     
     
         15 . The method of  claim 12 , wherein the cells are eukaryotic cells. 
     
     
         16 . The method of  claim 11 , wherein the eukaryotic cells are yeast, fungal cells, animal cells or cell lines. 
     
     
         17 . The method of  claim 11 , wherein step (d) comprises altering one or more genes in the eukaryotic cell. 
     
     
         18 . The method of  claim 17 , wherein altering comprises introduction of a gene or genes into the eukaryotic cell. 
     
     
         19 . The method of  claim 17 , wherein altering comprises modification of an endogenous gene or genes in the eukaryotic cell. 
     
     
         20 . The method of  claim 11 , wherein the biochemical reaction network comprises a substantially whole biochemical reaction network.