I think I just came up with the most effective anti-spyware method in existence!
Multiplayer.
As much time and money it costed to get SecuROM into the game, they could have just as easily spent that money into coding a multiplayer aspect to the game. How many people do you see pirating Guild Wars and Counter Strike:Source?
The online play would have to be worthwhile and not simply tacked on. Not sure if Bioshock is a game for multiplayer either, even if the dev team put many dedicated hours into it. Then again, I have only played the demo.