Requiring fifty rather than sixty votes is one obvious response, but let's say that either isn't possible or is for other reasons undesirable. That is, you still might want a high threshold for new legislation, yet without so empowering the sixtieth legislator or for that matter the fiftieth legislator.
One (non-practical) option is to randomize the number of votes held by each Senator, with the number being revealed only after the vote is held. That way Joe Lieberman wouldn't know in advance that he is the decisive Senator. One problem of this is that to ensure passage of the now-riskier bill you might have to spread around pork more generally.
Another (non-practical) solution is to give more votes to Senators who precommit in advance to supporting (or opposing) whatever comes out of the process. Of course that can also backfire, by making it harder for the non-Liebermans to threaten defection.
Then there is bribery and log-rolling and yet more pork.
What other options are there for limiting holdouts, either practical or purely theoretical?