Notes due to very helpful and relevant comments:

I will not be using mods in this playthrough, just to reduce risk of being unable to play/record if updates cause any issues, and because I want to be able to share the seeds + maps with other people if they want to check it out without requiring them to use mods. If we want to be more accurate, I guess this would be "what's the hardest run without using mods?" because you could use all kinds of mods that would make it virtually impossible :D

Chapters!
0:00 Intro
0:46 The "Hardest" Runs
3:07 Finding the Hardest Asteroid
6:06 Finding a Terrible Map Seed
12:33 Difficulty Settings
14:28 100% Achievements
16:13 Duplicant Restrictions
16:57 Additional Restrictions
17:46 What's Next?