Isolation. Isolation will likely be inevitable is early deep space missions. Space is vast and distances to other planets are bafflingly large. And, problems of stress, crew health, and crew interactions remain unsolved problems. Germs, disease and bacteria remain health problems with isolation. Communication and many other human factors are also unsolved problems with isolation in space flight.

Distance from earth. The distances that humans will need to traverse to go to places like mars and beyond are vast. No human has traveled so far and for so long while isolated in a small spacecraft. Our current propulsion technologies are primitive and wholly inadequate to achieve speeds that would allow for shorter travel times to mars and beyond. Round trip times remain over 24 months at the very least. And, the distance of other celestial bodies  ...