Serena, the daughter of League of Nobles Viceroy Manion Butler and his wife Livia, was a strong voice for the human rebellion at a young age. She was romantically involved with Xavier Harkonnen, who led the military force on the League capital world of Salusa Secundus. As the story began, Xavier was repelling an attack on the planet by Omnius' army of cymeks, fearsome weaponized machines controlled by disembodied human brains.
In 203 B.G., Serena was captured by the machines and put under the watch of Erasmus, an independent robot on Synchronized Earth who sought to understand humans completely so that the thinking machines could be truly superior. Unfortunately, his methods of study often entailed human vivisection and torture. Erasmus took a liking to Serena, as did the young Vorian Atreides, a human trustee working for the machines. Serena realized she was pregnant with Xavier's child, and later gave birth to a baby boy whom she named Manion (after her father). Erasmus eventually found this distraction inconvenient; he not only removed Serena's uterus, but killed her young son in front of her and his slaves by dropping the child from a high balcony.
This single event incited the entire Jihad against the machines. Seeing Serena subsequently attack and destroy a sentinel robot with her bare hands encouraged Erasmus' slaves, already groomed for rebellion by slave leader Iblis Ginjo, to rise up. Vorian, witnessing the murder and realizing the lie he lived as a machine trustee, betrayed his machine masters and fled with Serena and Ginjo. Young Manion was soon labelled the first martyr, Manion the Innocent. The first human victory of the so-called Butlerian Jihad was the destruction of Earth and the Earth Omnius using atomics.
As Dune: The Machine Crusade began, Ginjo (now Grand Patriarch of the Holy Jihad) and Serena (Priestess of the Jihad) had become the religious leaders of the human rebellion, and Xavier and Vorian its two generals. Xavier, thinking Serena was dead instead of a captive, had married her sister Octa and started a family. In 191 B.G., Ginjo created the "Seraphim", an elite force tasked with protecting Serena. She became interim Viceroy in 190 B.G. on her father's retirement, but was later relegated to a figurehead by Ginjo as he consolidated his power.