In silico constraint-based strain optimization methods: the quest for optimal cell factories

Shifting from chemical to biotechnological processes is one of the cornerstones of 21st century industry. The production of a great range of chemicals via biotechnological means is a key challenge on the way toward a bio-based economy. However, this shift is occurring at a pace slower than initially expected. The development of efficient cell factories that allow for competitive production yields is of paramount importance for this leap to happen. Constraint-based models of metabolism, together with in silico strain design algorithms, promise to reveal insights into the best genetic design strategies, a step further toward achieving that goal. In this work, a thorough analysis of the main in silico constraint-based strain design strategies and algorithms is presented, their application in real-world case studies is analyzed, and a path for the future is discussed.The work of P.M. was supported by the Portuguese Science Foundation (FCT) through Ph.D. grant SFRH/BD/61465/2009. We thank the FCT Strategic Project of UID/BIO/04469/2013 unit, the project RECI/BBB-EBI/0179/201 (FCOMP-01-0124-FEDER-027462) and the project “BioInd-Biotechnology and Bioengineering for Improved Industrial and Agro-Food Processes,” (NORTE-07-0124-FEDER-000028) cofunded by the Programa Operacional Regional do Norte (ON.2-O Novo Norte), QREN, FEDER, and the project “DeYeastLib-Designer Yeast Strain Library Optimized for Metabolic Engineering Applications” (ERA-IB-2/0003/2013) funded by national funds through FCT/MCTES