A lot of people are saying that you can't really make any significant changes because that would make a lot of plugins and themes incompatible with it. Well I say, keep Wordpress as it is but create a new version and invite some of the most popular theme and plugin authors to create their most popular themes and plugins for it before 'Ghost' goes out to the masses. Once people see how great it is, others will follow.
I personally think this is a really good idea however, I wouldn't remove the comment system.
I'd like Wordpress to be more flexible than it already is. I see websites like The Verge and Polygon, how they have different styles for different kinds of posts. They create beautiful reviews, very magazine-esque, how it's supposed to be. Giving this amount of control the users would allow authors to be a lot more creative and create even more beautiful and better websites than ever before.