Following the kidnapping of Leo Fitz, Phil Coulson, Alphonso Mackenzie, Melinda May and Jeffrey Mace by Aida and their replacement by Life-Model Decoys, Jemma Simmons and Daisy Johnson infiltrated the Framework in order to retrieve and rescue their friends. However, what they found was a world where fundamental changes to the kidnapped agents' lives had separated them and resulted in HYDRA establishing a dictatorship. On account of the unexpected dystopia they had stumbled upon, they tried to go back to the real world in order to figure out a plan; however, Aida had sabotaged their backdoor, leaving them trapped. Upon learning that Holden Radcliffe, the creator of the Framework, was also present in the virtual reality, Simmons and Coulson took a Quinjet piloted by Grant Ward and went to Ogygia, an island where the fallen scientist lived with his girlfriend Agnes Kitsworth.
Grant Ward, Jemma Simmons and Phil Coulson quickly found Holden Radcliffe playing in the gardens of his new residence. Simmons confronted him about the events which had taken place in the Framework. Fearing that they might be discovered, Ward suggested to take Radcliffe with them and go back to the Playground. However, Simmons would not listen and continued interrogating Radcliffe, asking him about how they could escape the alternate reality. After admitting that it was nearly impossible, Radcliffe explained that Agnes Kitsworth and himself were truly trapped in the Framework since their physical bodies were deceased. Therefore, the Framework was the only possible life for both of them.
The conversation was interrupted by the arrival of the Zephyr One, which transported Madame Hydra, The Doctor and several HYDRA agents. Radcliffe told the S.H.I.E.L.D. agents to hide while he dealt with the HYDRA team. Madame Hydra remained with Radcliffe while The Doctor took two men in order to search the subversives they were looking for after receiving an alert indicating that the non-flying area of Ogygia had been breached.
Radcliffe confronted Aida about what she had done with the Framework, leading to a world where HYDRA had put in place a reign of terror. When Radcliffe accused Aida of lying, she answered using the exact same words he had told her days before, that sometimes a lie could save lives. In the meantime, The Doctor found Agnes Kitsworth and brought her before Madame Hydra and could not help but notice her exact resemblance with the head of HYDRA. Madame Hydra explained that Radcliffe came from "the other side" and that he had enslaved her, triggering The Doctor's anger towards him, and accused the fallen scientist of planning to replace Madame Hydra with copies.
Distressed, Radcliffe tried to explained to The Doctor that neither Kitsworth nor himself represented a threat for HYDRA. Disbelieving him, The Doctor took the weapon of a HYDRA agent and threatened Kitsworth with it, telling Radcliffe that he had to convince him if he wanted his girlfriend to live. Unbeknownst to them, they were watched by Grant Ward, Jemma Simmons and Phil Coulson. Ward had a shot at The Doctor but Simmons refused that he killed him since it would also mean the death of the real-life Leo Fitz.
Radciffe further explained the situation to The Doctor, trying to have Fitz remembering details of their past friendship in the real world. When The Doctor mentioned Simmons, Radcliffe mentioned how deeply she and Fitz were in love in the real world. However, all these attempts were done to no avail when The Doctor claimed that his work in HYDRA was his true nature and, to make his point, he murdered Kitsworth in cold blood right before Radcliffe's eyes.
Upon seeing this, Simmons screamed in terror while Radcliffe was utterly shocked. The HYDRA operatives exchanged bullets with the S.H.I.E.L.D. agents, leading to the death of 4 HYDRA agents. Ward, Simmons and Coulson then returned to their Quinjet and left Ogygia while Madame Hydra and The Doctor took Radcliffe into custody at the Triskelion.
Following the standoff, Holden Radcliffe was imprisoned at the Triskelion, in a cell adjacent to Daisy Johnson's. Since he had nothing else to lose after the death of Agnes Kitsworth, Radcliffe told Johnson about a backdoor he had built in the Framework and that Aida could not remove, thus ensuring the later rescue of all the S.H.I.E.L.D. agents who were trapped in the alternate reality, except Alphonso Mackenzie.
The assassination of Kitsworth heavily traumatized both Jemma Simmons and Leo Fitz. While the former was well aware that the Leo Fitz she saw in the Framework was not the real person she loved in the real world, she was deeply affected by the sight of her boyfriend shooting an innocent woman in cold blood; as for the latter, he only realized the horror of his deeds once he was out of the Framework, and this murder, alongside with the death of the Patriot, made Fitz have doubts about his true nature that he believed could be evil.