Arianus has the most going on. I agree that you should base things out of here.
Pyran is exciting and boring. Exciting in that the Tytans can kill you at any second. Boring because they womped everything else.
Abarrach is pretty freaking deadly. Mensch won't survive here very long without aid. Not to mention all the undead.
Chelestra is the exact opposite, very friendly but also very dull.
... and everything else is closed off to the mensch.
What to do? Make stuff up.
A mensch based game could focus on trying to re-build trade between the four worlds (as was originally intended) without the use of the Death Gate being fully open (as was NOT originally intended).
The first step might be a exploration into the other worlds. An attempt to go to Abarrach might have been done before the party is hired so Arianus knows that world is deadly. Chelestra, of course, will accidently destroy any magic that holds mensch ships together. So start out with an expidition to Pyran. Put lots of made up monsters in there. The Tytans don't have to be the only guardians, they may have been the only ones that were indestructable.
But once the party discovers the indestructable Tytans ... toss in a coupld of weapons that can kill Tytans that Alfred and Haplo simply never found ... BUT they are on Abarrach! Now the party has a reason to go there, but how to survive? The secret could be in the waters of Chelestra.
How's that for a start?