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During 1850 and early 1851, Harriet Beecher Stowe read every slave account she could get her hands on. She interviewed dozens of ex-slaves and even began a correspondence with perhaps the most famous ex-slave in the country–Frederick Douglass. For her first novel, Harriet Beecher Stowe did a great deal of journalistic work. Uncle Tom's Cabin painted an authentic portrait of slave life on Southern plantations.

In May 1851, the first chapter of Uncle Tom's Cabin appeared in National Era as "Uncle Tom's Cabin: or, the Man That Was a Thing." Each week, Harriet sent a newly finished chapter off to her editor, who promptly published it in the next issue of National Era. This process was fairly standard for novels of the day–Charles Dickens, for example, published almost all of his novels serially. The book grew and grew and, in March 1852, the last installment of Uncle Tom's Cabin appeared in National Era. That same month, the book was published in whole and, like the each issue of National Era that contained an installment of Uncle Tom's Cabin, it sold out almost immediately. Uncle Tom's Cabin had captured the attention of an already tense nation.

The immediate success of Uncle Tom's Cabin was overwhelming. The book sold three thousand copies in its first day and went through 120 editions in its first year. Before the end of the year, 350,000 copies of the book had been sold and it had been translated into forty languages. Four months after Uncle Tom's Cabin was published, Harriet Beecher Stowe–who had, for so many years worked to make ends meet–received her first royalty check. It was for ten thousand dollars. In 1852, this was an almost incomprehensible amount of money.

In 1852, everyone in America seemed to have a copy of Uncle Tom's Cabin in his or her hand. The story of slave plantation life, the pathos with which she infused the lives of both slave and slave owner, and the impassioned argument she made against slavery evoked intense emotions in anyone who read it. The hero of the book, an old slave named Uncle Tom, is a gentle, affable, religious man who has been a lifelong victim of the institution of slavery. Later, in the mid Twentieth Century, the character of Uncle Tom would come be seen as a cliché of the obsequious, submissive black man oppressed by whites or white dominated society. But in Stowe's book, he was meant to be a living symbol of the effect of slavery on the human spirit. Uncle Tom finds his counterpart in the fiery George Harris, a younger slave who would rather die than remain in chains for the rest of his life. Stowe also created very real, complex characters out of the slave traders, the plantation owners, the apologists in Northern churches and the "conductors" on the Underground Railroad, mostly Quakers. The book made Harriet Beecher Stowe one of the most hated people in the South. The hostility was violent and unyielding despite the fact that Stowe had gone to great pains to show that Southern plantation owners were, in a sense, also victims of the institution to which their economy was wedded.

Harriet Beecher Stowe's social document was also regarded as great literature by some of the best authors of the time. Dickens was impressed by Stowe's book, Henry Wadsworth Longfellow considered it a triumph, Tolstoy called it "pure, moral art" and Henry James greatly respected it. In later years, when realism had trumped the maudlin romanticism of much of nineteenth-century American novels, Harriet Beecher Stowe's works would be seen as sentimental and clichéd.

By the end of 1852, Harriet Beecher Stowe was a full-fledged celebrity, both at home and abroad. Her financial worries were over, and she had acquired the fame she had long sought. However, her domestic duties were still of great importance to her and when, that same year, her husband Calvin Ellis Stowe was offered the prestigious chair of Sacred Literature at the Theological Seminary in Andover, Massachusetts, she welcomed the opportunity to cease being the chief breadwinner in the family.

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