When Ryan initially noticed Lamb's political influence he agreed to a series of publicized debates with her, hoping to ruin her popularity by exposing the weaknesses in her philosophy. This was a miscalculation on his part, and it only increased the number of her supporters. At last Ryan began to fear her influence, and he commissioned Augustus Sinclair's company "Sinclair Solutions" to monitor her and her followers, hoping to find an excuse to take her into custody. Stanley Poole of the Rapture Tribune acted as an undercover spy for Sinclair, becoming one of the "Rapture Family," Lamb's followers. Eventually Lamb was taken by Ryan's men and locked away at Persephone, a prison complex owned by Sinclair.
Once Fontaine Futuristics was able to produce ADAM in a massive scale, the marketing of gene tonics and plasmids (developed by Dr. Yi Suchong) went mainstream, selling to any individual that could afford them. These tonics and plasmids allowed individuals to do superhuman things, such as create fire at their fingertips (Incinerate!), release a swarm of bees from their arms (Insect Swarm), or increase muscle tissue and movement speed (SportBoost). Originally, Andrew Ryan enjoyed the success of Frank Fontaine, citing him as a prime example of the type of individual that should be inhabiting Rapture.
A few years passed, and Andrew Ryan began suspecting Fontaine of various crimes, ranging from smuggling to murder. A full-scale genetic arms race broke out between Ryan and Fontaine, as Fontaine's monopoly on ADAM threatened the current social structure. Andrew Ryan then attempted to arrest Fontaine; but Fontaine decided that he himself wanted to go down "guns blazing" and faked his death during the shootout in late 1958. After this, Andrew Ryan assumed control of Fontaine Futuristics, and began to produce plasmids and tonics within his own company, Ryan Industries. Tightening his grip upon the city, Ryan began instituting harsher punishments against problem citizens, arresting many of Dr. Lamb's followers.
Rapture was filled with civil unrest in the following months as Fontaine stepped into his Atlas persona, rallying the people who had flocked to his poor houses in subtle guerrilla warfare against Ryan's security forces. To combat this threat Ryan adjusted the Little Sister program to send the little girls out into the streets to gather ADAM from corpses. Ryan also commissioned Dr. Suchong to develop protectors for the girls, taking many of Lamb's imprisoned followers from Persephone and modifying them into prototype Big Daddies. To supply even more ADAM for the growing need Ryan's men began kidnapping little girls to turn into Little Sisters. After Suchong's accidental death by a prototype Big Daddy, the Protector Project was placed under the control of Gilbert Alexander, another brilliant scientist from Fontaine Futuristics. He finally completed Suchong's work by bonding Eleanor Lamb, daughter of Sofia Lamb, who was abducted and turned into a Little Sister, to Subject Delta. They became the first ADAM gathering couple working in Rapture.
The minor skirmishes reached a climax on the New Year's Eve of 1958, when the disenfranchised citizens who supported Atlas attacked various key locations in the city, including the upper-class Kashmir Restaurant. This event was the first large-scale battle of Rapture's Civil War.
Prior to the New Years riots Sofia Lamb had escaped from Persephone and was searching for her daughter. On New Year's Eve she and a few loyal splicers finally captured Eleanor from her protector. Delta was incapacitated by the Hypnotize plasmid, with which Sofia Lamb forced him to kill himself in front of a shocked Eleanor. Lamb then retreated back to Persephone with her daughter, avoiding the conflict of the war.
Throughout the Civil War, citizens and Splicers who were skilled enough to take down a Big Daddy learned how to retrieve more ADAM from the Little Sisters, harvesting, which resulted in the girl's death. Dr. Brigid Tenenbaum then felt something about the girls she turned into Little Sisters. She also noted how despite the mental conditioning, they are still and act like small children when they sing and play. Finally, Tenenbaum was confronted by a Little Sister in Farmer's Market. The Little Sister then came over and sat in Tenenbaum's lap, resulting in Tenenbaum pushing her off. She felt like she had strong hatred against the girl with the disgust in her. Tenenbaum then realized, it wasn't the girl she hated, it was herself. Tenenbaum then saw the error of her ways, she then made a Plasmid of her own that would kill the slug inside the Little Sisters, turning them back into humans, but only retrieving half the ADAM rather than harvesting. Tenenbaum then began to collect the girls she rescued and continued to do so, but no where in Rapture was safe. Eventually, she did manage to find an underground safe room in the sewers of Olympus Heights, keeping her and the girls safe from harm or the Splicers. Vents were then made into the safe house, so Little Sisters may find themselves safe and rescued by Tenenbaum. After being characterized as a monster for taking enterprise, Tenenbaum then hid away from the public into the safehouse until Rapture fell.