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Going where no show has gone before
Most TV shows atrophy due to (1) the premise of the show having been played out and/or (2) the principal actors feel no longer challenged by the material.
I would like to propose a series of "growth" development for the principal actors. These developments are grounded in the existing character portrayals.
Howard: After the death of his mother, he gets a visit from the family rabbi. He gets more interested in his faith and works to become a Reformed rabbi himself. He gets his doctorate in theology, hence; he now knows one more doctor. The conflicts/humor lies in the questions, "Is a doctorate in theology a real doctorate"? His heightened Jewish awareness plays out humorously in his day-to-day interaction with the other non-Jewish characters?
Bernadette: She financially supports Howard in his journey to be come a Reformed rabbi. Her conflict/humor lies in her portrayal as a "good" Jewish wife with her upbringing as a good Polish Roman Catholic.
Penny: She becomes an elementary school teacher with support from Leonard. She finds this career highly satisfactory. She stars in a number of summer stock performances for which she is constantly receiving rave reviews. She is forever reassessing her choice as a schoolteacher. This conflict serves as gist for Penny's humor.
Sheldon gets a Nobel nomination for a proposed and highly exotic but non-eloquent hypothesis. His proof taking his opus from hypothesis to theory is not overly convincing to the Nobel committee. He is in constant stress whether he will win or not. His every waking moment is fixated (humor) on will he or won't he be awarded "the prize". His angst is only exacerbated by....
Eventually Leonard is charged by the university to test Sheldon's theory and is able to answer/stumble upon a clear/eloquent solution to Sheldon's non-eloquent proof allowing Sheldon's theory to be accepted by the scientific community. Leonard is not only nominated but is co-awarded the Nobel Prize in science for his proof of Sheldon's theory. The conflict/humor arises between Leonard and Sheldon as to who really deserves the prize.
Amy as a neuroscientist working with monkeys has stumbled upon a simian chemical compound that releases human inhibitions and accidentally spreads the compound to Sheldon. This is directly responsible for removing the last mental barrier from Sheldon enabling him to develop his nearly Nobel winning hypothesis. This inhibition-releasing compound also induces Sheldon into a nearly physical relationship with Amy. She is constantly tinkering with the compound to make it just a bit more potent.
Raj and his attorney sister form an educational out-sourcing company. Some of what they are attempting to out source to India are courses presently taught by the university. As a result the departments under which both Sheldon and Leonard are working come under review for outsourcing as the university considers Raj's proposal.