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In 2005 Lowe starred in the miniseries Beach Girls on the Lifetime network, based on the Luanne Rice novel of the same name.The series premiere received the highest ratings for a movie premiere in Lifetime history.In an episode broadcast on May 16, 2010, his character was part of a multi-vehicle crash involving a large truck and was put into a coma, the storyline was wrapped up in the first episode of the fifth season; Lowe did not appear in the episode.In June 2006, he was the guest host for an episode in the third series of The Friday Night Project for the United Kingdom's Channel 4.During the final season of The West Wing, Lowe returned to his role of Sam Seaborn, appearing in two of the final four episodes.In 2011, Lowe appeared on The Oprah Winfrey Show and stated that he left the show because he did not feel he was being respected, when the other lead characters received a raise and he did not. In 2005, he starred as Lieutenant Daniel Kaffee in a London West End production of Sorkin's play A Few Good Men, the first time the two had worked together since The West Wing.After leaving the show, Lowe was the star and executive producer of a failed NBC drama, The Lyon's Den (2003). Although Lowe had expressed unhappiness about his decreased role on that show at the time of his departure, he has now repeatedly said that any animosity between them is over and that he was pleased to be working once more with Sorkin, whose talents as a writer Lowe highly regards. Derek Shepherd of Grey's Anatomy, which eventually went to Patrick Dempsey.
Thereafter, his film career decreased and he ventured into television, making his breakthrough as Sam Seaborn on the NBC political drama The West Wing (1999–2003), for which he received a Primetime Emmy Award nomination and two Golden Globe Award nominations.
As an American POW, his ancestor was given a choice, and took the option to stay in the United States.
In California, he attended Santa Monica High School, where he met Charlie Sheen.
When the show premiered, Seaborn was considered the lead, and the pilot centered on the character.
But the acclaimed cast of the show—including Allison Janney, Richard Schiff, Dulé Hill, John Spencer, Bradley Whitford, Martin Sheen (whose President Bartlet was initially scripted as a small role) and Stockard Channing (whose First Lady was initially scripted as a guest role)— were all strong actors and eventually Lowe's character was no longer the lead.