Before discussing more complicated systems, it is essential that the general requirements for and consequences of achieving a non-equilibrium steady state are clear. In Box 1, we develop the universal features of such systems using a simple chemical example and mathematical equations. Our key conclusions are: i. For a reaction network to achieve a non-equilibrium steady state it must be coupled to a spontaneous process (i.e., the relative concentrations of the species involved in the coupled process do not accord with the corresponding equilibrium constant, here Krxn throughout). 17 ii. Coupling between the network and the spontaneous process requires that species in the former mediate the latter. iii. Even if conditions i. and ii. are met, the relative concentrations of species in the network will not be perturbed unless the network displays kinetic asymmetry. 13f iv. At non-equilibrium state, the relative concentrations of species in the portion of the network coupled to the spontaneous process can be perturbed from their equilibrium values and net flux take place between them but species outside the portion of the network coupled to the spontaneous reaction are unaffected. If conditions i-iii are met, net flux between species in the coupled cycle can be harnessed to do continuous work at steady state. Point iv. highlights that it is not informative to describe the whole system as "out of equilibrium"only some parts of the system are affected by the coupled reaction. Finally, we emphasize that the second law remains intact as, if the free energy change for the net process is determined (i.e., following the pathway of net flux), it will always be found to be energetically favorable.