Following the Challenger explosion, they changed the seal design to prevent leakage. From all that I've seen, the problem was fixed. Now, the problem is foam chucks falling off the ET and damaging the heat shielding. How about fixing that problem? You can change the foam composition, how it is applied, and how it is inspected.

Of course, if you operate the Shuttle long enough, other failure types will manifest themselves and another Shuttle will likely be lost. While they've been preparing for return to flight, they've been examining and hopefully fixing other possible failure modes. Still, odds are there are still unpredicted failure modes in the Shuttle design that will catch us by surprise.

"Those who fail to learn from history are doomed to repeat it; those who do learn will find new ways to screw up."

As for a one-way mission to Mars, similar proposals were made for sending people to the moon back in the 1950s and early 1960s. In today's excessively risk adverse society, I think the odds on such a mission are much less than back then.