This seems to be the path taken by Paul Graham and Robert Morris (just to name an obvious example most readers here will know). Because they knew a lot about Computer Science (and Lisp), they were able to take an approach to building their software and business that their competitors would have never considered. I'm guessing their knowledge of "science, philosophy, history, art, etc." played a big part in their approach, as well.

Which is to say, I think you're on the right track if you don't just want to follow the popular trends, but want a chance to do something new in a way that no one has even considered yet. Which certainly sounds a lot more fun, if nothing else.