The tribes tried to fight the encroachment by the colonists. Major conflicts took place in the Indian massacre of 1622 and the Second Anglo-Powhatan war, both under the leadership of the late Chief Powhatan's younger brother, Chief "Opechancanough". By the mid-17th century, the Powhatan and allied tribes were in serious decline in population, due in large part to epidemics of newly introduced infectious diseases, such as smallpox and measles, to which they had no natural immunity. The European colonists had expanded territory so that they controlled virtually all the land east of the fall line on the James River. Fifty years earlier, this territory had been the empire of the mighty Powhatan Confederacy.