It should all be oriented around controlled socialization. It shouldn't be WoW in space. It shouldn't orient (chiefly) around combat, and in-game currency shouldn't be some bullshit resource like other MMO's -- tusks, or ore, or whatever.
It should be favors. Jobs. Work. Players should be in various positions of control and leadership, with no hard level structure. Everybody has their own things they need to get done, to advance as a character, which requires them to seek out the help of other players.
Say you're a Quarian. Your job -- and how you progress as a character -- is the upkeep and improvement of the Migrant Fleet. What can you add to it? How can you protect it? Everybody votes -- what system should we move the fleet to this week?
Say you're a Krogan. You don't give a shit about the big picture -- it's about you and the 15-30 other bros in your clan. Who are we fighting? How do we expand our borders? Maybe we don't like the direction our Battlemaster is taking us -- can we ban together, kill him, steal his money, and hop a spaceship out? Maybe we'll start a mercenary band.
-------------------------------------------------------------------------------------------
Combat and death should not be everyday events. They should only occur under specific circumstances.
Say you're a little (no levels, but the equivalent of) a level 1 Krogan, with your clan in Tuchanka. You can't just draw your gun on anybody you want and engage in combat; that would be anarchy. You can only kill people your battlemaster has marked as targets.
But attempting to do so opens you to the risk of death: with your own willing consent.
Now say your clan battlemaster is putting together quests for the clan. He wants to send five of you to take this (instanced) hospital from another clan, to expand your territory. He gets a little notification -- "Warning: Putting krogans in your clan on this mission will expose them to risk of death." And he has to think about that. And YOU have to think about it, when you accept the mission.
When you die, you're dead. But because there's no hard level system, and because combat and death is ALWAYS a carefully-calculated scenario where all parties involved know what they're getting into, any time you die, it's the result of a series of choices you made.
Battlemaster sent you into a mission way above your ability to handle? Should have grown a quad and told him so, or brought some more friends along. Quarian killed you in a bar? Well maybe you shouldn't have murdered his wife on that space station a year ago.
And again, it comes back to social links and role-playing.
Kill somebody, and anybody registered as a "friend" to them gets a notification, can declare you an enemy, and now has the ability to go weapons-free on you if they ever spot you in public.
Do you really want to kill this Quarian engineer, who claims she has friends in the Admiralty? Maybe she's bluffing. But then again, maybe somebody could shoot you in the back a year from now. And at any rate, if you don't kill her, you're going to have to deal with the fallout among your clan.
Decisions, decisions!
----------------------------------------------------------------------------------------------
No global /tell features or anything like that. Travel and communication are tightly designed features within the context of the game.
Everything should be done by players, for players, through players. It's all about using social links to create emergent narratives.
Say you're a drell, and some Krogan (another player) kills your wife (also another player). How do you deal with that? Well, he's in a completely different star system, so you shoot him an email on the extranet, demanding an explanation. He doesn't respond.
So you email a friend on a nearby planet -- "can you go check this out for me?" He says sure thing, because you helped him rescue his friend from that slaver crew that one time. He finds out the krogan who killed your wife is living on Omega, and so he pays a local mercenary leader to keep an eye on him -- who pays some underlings to do it.
And all the way down at the end of the line, it boils down to an "observe and report" quest.
So now your goal is to get to Omega and kill this guy. Only word gets down the grapevine that he's a battlemaster and has ten krogans underneath him. So now you're trying to call in favors, build a team from your friend, raise the money to charter a spaceflight, and get to Omega to mete out some revenge.
And because this is all just players, maybe that changes once you get there. Maybe you walk into the bar where this guy is and there's a huge fight about to go down, and he asks for forgiveness, and offers to pay you. Or maybe you two become friends, and start working together.
And however it gets resolved, you've just spent the last month in a very interesting personal story, rather than dicking around farming crystals or mining ore or whatever.
-------------------------------------------------------------------------------------------
Down the line, once players are migrating away from their native social systems (high-level krogans leaving their clans, Quarians saying "eh, screw this" to the Migrant Fleet) you introduce a colonization system. Players get together, find an empty, habitable planet, take some resources there, buy some construction mechs, and start a colony. They put someone in charge. They vote on the basic direction they want to go, and then they start building.
In order to expand, they need to clear zones of the planet. Clear a zone, and you can attach a new building there. Which is just an instanced environment. You can accomplish a lot, design-wise, with carefully-controlled instanced environments.
Except clearing the planet necessitates clearing out thresher maws and other nasties. Which requires the hiring of mercenaries, who can do it as a "kill five thresher maws" quest. Which requires money. Which requires buying/selling/sharing resources with other colonies nearby.
Now, obviously it shouldn't be anything like an EVE-level of craziness, but the idea is that, since the game is oriented around social systems with favors and work at the core, an infinite number of planets to be colonized are, essentially, engines which produce an infinite amount of work TO BE DONE.
-------------------------------------------------------------------------------------
There probably shouldn't be a space-game -- at least not in the sense of people whipping ships around like fighter pilots, flinging lasers and missiles at eachother. Number one, because it's resource-intensive, and number two, becuase it's not what the ME universe is about.
Travel takes place in real-time, similar to the airships in FFXI. Book a flight to another planet, and you need to be on that ship before it leaves. And then it's a two-day journey from your planet to the nearest Mass Relay -- during which time you're inside an instanced space-ship, with all the other passengers.
Maybe down the line you get your own ship (NPC crew handles the minutae). Now you're free to live on your ship in space, if you so choose -- but you have to pay attention to fuel, food, etc. Travel still takes time, but now you're free to chart your own course at any point you choose.
So say you buy a ship, and you want to go exploring empty planets. You invite some friends aboard, and your little ship of fools sails off into the stars.
You log in to Mass Effect Universe mid-transit -- so your character wakes up, aboard the ship. You talk to your friend, who owns the thing. He tells you you've got about a day and a half until you reach the Charon Relay. So you grab some food from the mess, and go sit by the big space window, and the two of you just sit there and talk for half an hour. Maybe you discuss philosophy. Maybe you trade social links; "You know a good engineer? I need to get the ship maintained soon." "Sure thing. But hey, do you know anybody with mercenary connections? I've got this thing I need to take care of."
Then you go back to bed, and log out.
---------------------------
tl;dr
The whole point is: don't make it WoW in space, with "collect five rachni hearts" as the standard unit of gameplay. Don't make every character the hero destined to save the galaxy.
When everyone is special, no one is.
Mass Effect is about role-playing, social links, and interactive character conflicts, with multiple sides to every story.
The game should be built in a way that facilitates players to live through these kind of stories in an organic way. To make a choice, and have it pay off -- or bite them in the ass -- a month, or six months, or a year down the line. Players should be encouraged to play multiple characters, in multiple races. Players should look back on their roster of dead characters and say, "That guy had a story from beginning to end. He did this, he did that, and then he died. That was a good story. I look back fondly, on having experienced all that. This is what I learned. This is what I'll do differently with the rest of my characters. I wonder what stories I'll live through next."