The search for the biological substrates of affective disorders spans many centuries. Indeed, Hippocrates (460–357 b.c.) speculated that melancholia emerged when environmental conditions, such as the alignment of the planets, caused the spleen to secrete black bile, which then darkened the mood. During the next 2,000 years, few significant contributions to our understanding of mood disorders emerged until Robert Burton's Anatomy of Melancholy (1621). Positing that depressed people often "are born of melancholy parents," Burton anticipated the genetic underpinnings of melancholia as well as other factors in the pathogenesis of depression, including alcohol, diet, and biological rhythms. Through his careful longitudinal observations, Emil Kraepelin (1856–1926) was subsequently able to detect a genetic contribution to manic-depressive illness. Kraepelin also hypothesized that other constitutional factors resulted in specific brain abnormalities in manic-depressive patients, although postmortem tissue studies were unrevealing.