Scaling up synthetic biology: Do not forget the chassis

Using comparative genomics and functional analysis, this work summarises how the cell's genome is organised, with emphasis on the importance of the cell's chassis. Some discrete but important engineering constraints are reviewed, beginning with the need for scaffolds, as well as the question posed by the difficult task of putting a very long random thread (DNA) into a limited volume. Subsequently, to illustrate overlooked essential functions, we show the importance of safety valves, as well as the need to cope with leftovers. The third section discusses how transplantation experiments point out a remarkable feature of the cell factory: the program replicates (makes identical copies of itself), whereas the cell reproduces (makes similar copies of itself), placing in the limelight the role of informational maintenance. A final section identifies the need to put together a globally linear behaviour of the cell with intrisically non‐linear genetic constructs. The discussion ends with the central question of evolvability of artificial constructs and to suggest that combining in vivo Synthetic Biology with biochemical reactors might be an efficient way forward.