The general success rate of breakthroughs is pretty damn low, and so I'd argue that most examples of "invalid" pessimism (excluding some stupid ones coming from scientists you never heard of before coming across a quote, and excluding things like PR campaigning by Edison), viewed in the context of almost all breakthroughs failing for some reason you can't anticipate, are not irrational but simply reflect absence of strong evidence in favour of success (and absence of strong evidence against unknown obstacles), at the time of assessment (and corresponding regression towards the mean rate of success). They're merely not as hindsight resistant as Fermi's example. You look back at history seeing things that succeeded. Go read archive of some old journals, and note the zillions of amazing breakthroughs that did not pan out.

If bomb did not rely on unusual U235 , Fermi would not have been irrational about 10% probability to emission of secondary neutrons from fission - it is something that most likely either happens for all fissions, or does not happen for any fissions, so the clever "there would be one" argument doesn't work irrespective of U235. U235 is not the most general valid objection, it's just the objection for which sources are easiest to find. No one did the silly task of writing out that production of secondary neutrons is not a statistically independent fact across different nuclei, and we're lucky that there's just 1 nucleus so we don't have to, either.