Balance suggestion: Perks that take up more than one slot
What if instead of constantly balancing all of the perks so that they don't become too powerful when mixed with infinite combinations of all of the other perks, the perks got re-worked so that some of them took up more than one slot?
Four-slot perks could be powerful and give you one super strong skill, but it would be the only skill you could bring. One-slot perks could be weaker individually but have more opportunity to combo. Two and three-slot perks somewhere in the middle.
That change would limit the possible combinations of perks so that the balance wasn't as delicate, and allow some individual perks have stronger/more useful/more dramatic, play-style changing effects.
Ex: Old Pain Res was annoying when people stacked it with other gen regression perks and ran it all of the time, but maybe if you'd had to run it solo or with only one other perk, it would have been fine.