PvE can stay interesting if there's a hard mode, or challenges, or different approaches, or a strong random element. I have won Nethack several times, but never twice in a row (or even close). The later games were not much less interesting than the first. I have played Final Fantasy 1 through several times with seriously different parties. That worked quite differently each time. For on-going challenge, there are speed-runs in a gradually changing environment (Kingdom of Loathing springs to mind). You can also mod a game much more simply than creating it the first time, and that can change quite a lot.

Now... how does this translate to Science?

Social science would be on a moving target, and so could stay fairly fresh. You can try taking different axioms in math and seeing what you get, that would be sort of a mod and sort of a different approach. I'm not sure what speed runs translate into. Mods would be alternate physics.