^ Where would the drama and adventure that makes up the show come from, where's the conflict?
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This is mostly not mentioned because I have a number of thoughts of how this could pan out with the same start point. However, the previously mentioned missing expedition would come into play at some point. Starfleet would have originally assumed attack by the Kelvans, but this would be part of an background story arc early on (possible signs of an unknown large scale threat).
Also, I have now got as far as reading mgummelt's idea earlier, and noticed some similarity. Particularly in how the new galaxy (probably Triangulum, but could be changed) is not populated mostly by humanoids. Triangulum would have a number of warring species/alliances with technological levels similar to TNG era or slightly earlier. Another ongoing arc would be starfleet trying to determine the causes of the disputes, as each side is convinced of completely different reasons. (Though things start to indicate that neither side is correct - related to the same threat that caused the disappearance of the Andromeda expedition).
I would have some change to the implementation of the prime directive, too. Although it is the default position of Starfleet itself, it is not on on the United Galactic Alliance's founding charter as it is on the Federations, and decisions can be made by the Alliance to give Starfleet orders to intervene in certain circumstances. There will be a number of episodes dealing with the moral implications of what can and should be done.
Another background thread would be the fact that the Galactic Alliance is not quite as stable as 23rd/24th century Federation, and the existance of the Federation as a separate entity would cause some of the problems. The minor members of the Federation feel that their membership gives them more clout in Galactic affairs than they would alone, but the larger members such as Earth/Vulcan and Andoria feel that they would have a better say as independant members of the Galactic Alliance.
Individual stories would consist of a general exploration type episodes as in earlier Trek, alongside those dealing with the internal politics of Triangulum and with the uncovering of possible threats to come.
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