Synthetic pathway construction

Cell factory optimization

Control of populations during fermentation

Challenge

For the development of novel bioprocesses novel pathways need to constructed. The identification of these parts (genes) is time consuming and relies typically on inteation between construction of a limited number of pathways followed by analytical screening. The limitations of this approach significantly contributes to the long develoopment time of cell factories as well as limits the spectrum of chemical products for which biological production processes are pursued.

Challenge

Once functional synthetic pathways have been constructed, they must be introducted and optimized in their host organism to create a consilidated cell factory. Substantial engineering of both the synthetic pathway and the host organism is required to identify cellular solutions that lead to competitive yields at high rates. This optimization effort is also limited by our current ability to separate highly yieldiing cell factories from the rest, since we again largely rely on analytical screening to make this distrinction. As a resultat, our approaches to cell factory optimization is currently constrained, limiting the benefit we can derive from new synthetic biology methods.

Challenge

In fermentation processes, the engineered cell factories typically show reduced productivity due to the rapid appearance of non-optimal phenotypes in the fermentation culture. This results from the divergence between the objectives of the fermentation process and the selection pressure for increased growth rate of clones within the cell factory population. From an evolutionary perspective the overproduction of a chemical product is not desired and as a resultat even engineered cells will evolve away from the production objective and towards a state of lower production and higher growth rate.

Approach

PROMYS will address this challenge by substituting the labour intensive and time-consuming analytical screening with ligand responsive selectioni systems that couple the intracellular presence of the desired chemical product to the survival of the cell. Using this technology millions of combinatorially desired synthetic pathway constructs can be tested in days compared to years using conventional analytical methods.

Approach

PROMYS will address this challenge by constructing ligand responsive selection systems that integrate multiple cellular cues that are signatures of optimized cell factories, including high flux and intracellular product information. These systems will facilitate a drastic increase in the number of cell factory constructs that can be adopted for biotechnological processes.

Approach

PROMYS will address this challenge by integrating ligand responsive selection systems into the cell factory that sense the cellular state and couple the output of such circuits to cellular programs that eitherfix such stresses in real time or destroy individual cells that do not fulful production objectives. In this way the fermentation population can be maintained in the desired state of high productivity resulting in higher fermentation yields.