Can you find a way of reducing this word puzzle to a manageable size?

I heard this puzzle on the radio this weekend (skip down to where it says next week’s challenge). I am not going to ask you to solve it. If you have an answer, you can submit it to NPR. The question here is how you can turn something that may initially seem to be impossibly difficult into something more reasonable. Without doing any linguistic analysis, what letters can you say with complete certainty must be in the solution word? Extra credit – how many possible combinations of letters are there, ignoring the order of the letters?