Hisae is Haruka's grandmother. Haruka's parents had no interest in alchemy and left the island. Hisae raised Haruka by herself and taught her alchemy. Hisae's first name is known only to a few people, such as Haruka, Mei, Natsume, and Miya. Most students simply refer to her as "the Principal". Hisae and Miya had co-operated on several large-scale alchemy experiments but Miya retired.
She founded the school with her husband Seibe many years ago. He passed away in an accident during the founding of the school and Hisae greatly misses him. They were searching for the Noblemen's Stone on the island when Seibe was killed during a cave-in. Hisae becomes the main antagonist in all paths but events taught her to move on.
Hisae greeted the transfer students at the island harbor. Kazushi later discovers a patch of white flower under Haruka's responsibility by Hisae's command. Later during the welcoming party, Hisae realized that the guys showered the cafeteria with the petals of the flower from that flower patch. She fainted twice from the shock and decides to expel them.
The girls then appeared to defend the guys and Hisae decided to make the next alchemy class produce fast-growing flower seeds. In that class, Hisae partners with Kazushi during the experiment and helped him produce it. She describes the process of alchemy as a unity of man and woman, and of death and rebirth.
One day, Hisae announced a school cleaning day. Hu-sen and Rei caused a fire at the alchemy laboratory and she punishes them to clean the school toilet and field. The guys defended them and took the responsibility instead.
Later, Rei attempted to frame Kazushi for stealing the exam question papers. The group refuses to reveal the truth so Hisae decided to punish them by making them watch over one of her experiments overnight. The experiment caused strange effects on the girls and Rin disrupted the experiment. Natsume appeared in a large beaker and she confronted Hisae regarding the experiment. Hisae does not reveal anything though.
On Haruka's path, Hisae reveals that Kazushi has a unique power. Later, Hisae lured Kazushi to and underground room where she was conducting an experiment to resurrect her husband Seibe by sacrificing Kazushi. Haruka lost her life to save Kazushi and Hisae realized the error of her ways and moved on. She shared her research notes with Kazushi as he attempted to resurrect Haruka.
On Natsume's path, Hisae stabbed Natsume in the heart with a knife. Kazushi later found out through Miya that the real Natsume was actually in a comatose state somewhere on the island. They searched and found Natsume and Kazushi woke her up. Natsume swallowed an incomplete Noblemen's Stone that Hisae and Miya was working on. Later, Hisae conducted a large-scale alchemy experiment to sacrifice everyone in the school to complete the stone. Miya confronted her and stopped her and she realized the error of her ways.
On Mizuki's path, Mizuki lost her legs to an accident. Mei explains that Mizuki's legs can be recovered using the Noblemen's Stone. Hisae reveals that she is also looking for the Noblemen's Stone. Hisae threatened to take Kazushi's life but Mizuki defended him. She then realized the value of relationship and shed tears that coagulated into the Noblemen's Stone. Hisae gave up the stone to Kazushi.
On Mei's path, Hisae warned Kazushi not to get close to Mei, hinting that trouble may result. When Mei suffered a heart attack, Hisae and Miya revealed that Mei is actually a homunculus and a product of their experiment. Hisae explains that Mei was designed to give her love equally to all her students but Kazushi has upset that balance by sharing a relationship with her. Kazushi and Mei decided to spend the remainder of their life together.
On Ran's path, Hisae was away from the island when Ran and Kazushi destroyed her underground alchemy experiment room.