Love him or loathe him, Sheldon is the star of the show. Without him, The Big Bang Theory simply wouldn't have exploded to the size it is now, therefore any ending to the show needs to heavily revolve around him. A Nobel Prize for a definitive scientific discovery would be a fitting end. It's unclear how this would work, with attempts to keep the show based on real science at all times, so the reasoning behind Sheldon receiving the honour may have to be purely based on science fiction, but that wouldn't matter. It would be a deserved end with some great laughs if it were to happen.
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