This is something so obvious that I don’t understand how I’m the first person I know of to say it: The hand is designed to work with the thumb and fingers in opposition. Therefore, modifier keys should go under the thumbs and the other keys under the fingers. Because the thumb can comfortably and easily oppose each of the four fingers it follows that each thumb should have four available modifier keys spaced to match that natural ergonomic.

The keyboards with a thumb cluster are a step in the right direction. Sadly, the positioning is suboptimal at best, because the design philosophy treats the thumb as just another stronger finger.