uncertainty
Explanation
This comic explores the question "How can you be certain you've lived a good life?" through an increasingly philosophical lens.
The first character states that a good life is obviously one made of lots of goodness. The second character points out that to get the sum of total goodness, you'd have to integrate goodness over a lifetime. Since the future is uncertain and you'd need to use an equation, there is no precise answer -- only a probability distribution.
The comic escalates further: the only way to know your current goodness is to self-assess, but measuring goodness alters the amount of goodness at a given moment (a nod to the Heisenberg uncertainty principle in quantum mechanics). This means that humans exist in a perpetual state of hedonic uncertainty -- a state that can't be altered, as it's a fundamental property of the universe.
The joke culminates with the two characters standing at the edge of a cliff (literally on the precipice of existential despair), when one suggests that maybe this is why engineers never study philosophy -- the implication being that overthinking the question of whether life is good can paralyze you, while a more practical-minded person would simply get on with living.
The humor comes from applying the formalism and conceptual baggage of quantum mechanics (uncertainty principle, measurement affecting the observed system, probability distributions) to the entirely subjective question of whether you're happy.