TL;DR: 1. Use the programmability and layers to your advantage; don't repeat old problems by overloading certain digits (the thumbs) with too many keys and lots of stretching;
2. Do-able: Reconfigure the hardware so the inner column has three 1u keys vertically, thereby moving the home position inboard and closer to the existing thumb clusters;
3. Not do-able: There will always be certain limitations of a two dimensional layout that doesn't allow movement in three dimensions like Maltron / Kinesis / Acidfire's Nexus. But changing that would result in a totally new keyboard.
Long version:IME, the Ergodox is a great improvement on a standard layout ergonomically; and also in terms of programmability -- which also helps with ergonomics, since it allows various functions to be accessed by staying near the home row and shifting through the layers rather than over-stretching the fingers (or in this case, the thumbs). I could never touch-type the top row (numbers / symbols / fn keys) on a standard layout, but the non-staggered ergodox layout is much more intuitive (your brain may vary) and now I'm pretty good.
I have small hands, but I have no problems with accessing the thumb clusters on the ergodox. As mentioned above, I have assigned the smaller thumb keys to lesser used functions, and to various Auto Hotkey macros such as automated file backups or google search on highlighted words, which naturally involve a pause in my typing / workflow. So I sometimes pause and look for those keys by sight; move off the home row; and take a moment to relax. But I can still hit them by touch when needed.
The various mods to the thumb clusters shown above seem to exacerbate the need to stretch the thumbs. Thumbs and associated tendons are not immune to stress from repeated stretching, and the layouts above place disproportionate emphasis on the thumbs and the need to stretch in a wide arc rather than a quick shift-and-tap with the present layout.
Instead of radical changes along two dimensions, the ergonomics of the dox would benefit more from incorporating curvature like a Kinesis or Acidfire's amazing work. But that would require so many physical changes that it would become an entirely new beast rather than an incremental change.
One way to make the general thumb cluster area more accessible is to move closer to it. By which, I mean moving the hands inward: replacing the existing 1.5u vertical keys with 1u keys that become the "new" homing keys [F and J, or whatever are the "bump" keys in your preferred layout] and then tweaking the "vertical stagger for finger length" of the plate mounts accordingly. For me, I rarely use those inboard vertical keys (to the extent that I can't remember what I have assigned to mine). Moving the home keys inboard not only gains one key per side (3 1u keys arranged vertically rather than two 1.5u), but it also gives one more vertical column on the outer edge, under the pinkies, for things that the current layout forces one to relocate elsewhere. On a Mac: [()'"/{}] etc. OnEuropean layouts, many of the umlaut characters, etc.
All IMO, of course (and under the influence of a couple of beers, so don't flame me

).
[edit]
As mentioned in a previous post, the v1 ergodox is a revelation for me, and keyboards of this style (and from this open-source origin) are surely the future: I have no intention of returning to a standard layout. Huge thanks to everyone whose talent and perseverance made it a reality.
I earn my living using a keyboard. I can type for extremely long periods on the ergodox without discomfort, whereas a long day on a standard keyboard now leaves me in pain (hence I jumped on the first dox buy). The sort of incremental damage that was noticeably harming my harm my health and career prospects. I DO have some "normal" keyboards on my "do want" list, But more because of the "n+1" theory, and not because I have any intention of reverting to a standard board as my daily driver.
Despite not being entirely convinced of the thumb layouts suggested here, I welcome any improvements to ergodox v2, as it has literally saved my ability to keep on working. Unless the rumoured new Kinesis is a radical improvement on the previous version; or unless Acidfire knocks everything else into oblivion, then constructive community discussion on the future iterations of this great project should be strongly encouraged.
(thanks for reading

)