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Virginia Johnson worked alongside William H. Masters as they completed research of human sexual response and sexual dysfunction beginning in the late 1950s. To learn about the characters they were portraying Caplan along with her other co-stars read Thomas Maier's 2009 biography Masters of Sex. The author also allowed Caplan to listen to some of his interview tapes with Johnson. Caplan also attempted to spend some time with Johnson before she died in 2013, but Johnson was ambivalent about the development of the show. It was the first time she portrayed a real person and Caplan mentioned in an interview that she felt a "deep responsibility" to Johnson, but that she had some wiggle room because most people have no idea what Johnson looked or sounded like. Maier stated that the developers of the show have remained mostly accurate to his book and have included other events that are historically relevant to St. Louis, where the series takes place and where Masters and Johnson lived. Caplan has discussed becoming comfortable with the large number of sex scenes in Masters of Sex.

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