Sadistic geneticist, Dr. Nathaniel Essex, opened the State Home for Foundlings, so as to experiment on the mutant genome. Above ground served as an orphanage, while, underneath the surface, there was a complex laboratory. Operating as the Orphanage owner, Mr. Milbury, Dr. Essex would monitor and test mutants, even keeping mutant children in cryogenic sleep in the basement, while attempting to create a powerful weapon against his estranged master, Apocalypse. After registering the potential power of Scott Summers, Dr. Essex, calling himself Mister Sinister, placed Scott and his brother, Alex Summers, in the orphanage, where they were subjected to a battery of tests and experiments. Both boys were adopted, but Sinister continued to monitor Scott.
It was here, that Sinister found that a union between Scott and Jean Grey (Marvel Girl) would produce the powerful mutant he was searching for. At the time, Jean was acting reckless, so Sinister created a clone of her, Madelyne Pryor. Sinister's plot was to produce a child from the union of Madelyne and Scott, whom he believed would become a genetically superior mutant. To Sinister's disappointment, Madelyne had no life and did not develop any mutant abilities at puberty as he had hoped, so he left her in her incubation tube as a failed experiment.
It was at the moment of the Dark Phoenix's death that a spark of the Phoenix Force was accidentally bestowed on Madelyne's body and renewed Sinister's interest.
After learning that Jean was alive, Sinister hired Maddie to fly a cargo to San Francisco for a large sum of money and, at the last minute, decided to take Christopher Summers, her son, with her. Mister Sinister, reacting quickly to Jean's return, aimed to eliminate Madelyne before the truth of her creation was revealed and sent his Marauders to kill her and kidnap her son. Maddie used her latent psychic powers to defend herself, but lost baby Christopher to her enemies. Sinister took Christopher to his secret lab hidden under the orphanage. There, Sinister experimented on Christopher. While Sinister was out, and, with clues from Destiny of the Freedom Force, Scott and Jean returned to his childhood orphanage and found the laboratory in the basement, with many children, including baby Christopher, in incubation pods. While attempting to rescue Christopher, Scott and Jean battled Nanny and Ophan-Maker, who were attempting to kidnap mutant children to safeguard them, for him. Maddie was taken, by N'Astirh, back to the orphanage and, in the basement, revealed a laboratory and an incubation tube with her name on it. In the lab, Mr. Sinister revealed himself and bound Madelyne, explaining her existence as Jean's clone to her. After being told that he would experiment on her, Madelyne used her considerable power to break free of Mr. Sinister's bonds. Christopher was also taken back to the orphanage and delivered into the hands of his mother, now calling herself the Goblin Queen, calling Christopher Nathan, and aware of her powers.
After being tricked into releasing the Legacy Virus, by Stryfe, Sinister spent most of his time in his laboratory, attempting to find a cure. Eventually, Sinister learned of a young mutant, Threnody, who had the power to sense death and decided to use her to help monitor Legacy Virus victims around the globe. Threnody stay-in the lab, while Sinister would do field missions and after he would return, familiarizing herself with the intricate systems. After months with no results on the Legacy Virus, Beast instructed Sabretooth, who was at the time a prisoner/patient at the X-mansion, for information on Mr. Sinister. Beast led a small team of X-Men, Rogue, Gambit, and Psylocke, to the orphanage. After defeating a poorly cloned Riptide and Sabretooth, the team found Threnody in a workshop, working to cure the Legacy Virus for Sinister. Beast refused to let her stay in Sinister's care, but Threnody promised the X-Men that she would work for them, while gaining Sinister's trust, stating they should leave before Sinister became aware of their presence, a move Hank disagreed with, but was forced to accept.
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