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A tailor's son, Gutzlaff, or Guo Shi Li, was educated at the school of Johannes Janicke, a Moravian preacher in Berlin. He did further studies at Rotterdam. His interest in China grew after a meeting with Robert Morrison in England. He sailed to Siam in 1824 as a missionary of the Netherlands Missionary Society (NMS). Within three years, he had translated the Bible into Thai and had learned the Fujian dialect from the Chinese settlers there. He went to Batavia (Jakarta), Indonesia, in 1826, where he met Walter Henry Medhurst and learned Malay and some Chinese dialects. He married Mary Newell, an English woman, at Malacca, Malaysia, in 1829. She died shortly after and left his a considerable inheritance. He married Mary Wanstall, a cousin of Harry Parkes, the future British minister at Beijing, in 1834. The second Mrs. Gutzlaff ran a school and a home for the blind in Macau. She died in 1849. Gutzlaff's third marriage was to Dorothy Gabriel in England in 1850.
Gutzlaff broke off with the NMS in 1828 because they refused to send him to China. He made several trips in the 1830s, sailing along the coast of China, traveling as far north as Tianjin, distributing Christian literature. He recorded his voyages in A Journal of Three Voyages along the Coast of china, 1831, 1832 and 1833. When Morrison died in 1834, Gutzlaff replaced him as an interpreter and secretary of the East India Company (EIC) in Guangzhou. While in Macau, Gutzlaff translated the Gospel of John and the Epistles of John into Japanese, with the help of Otokichi, Kyukichi, and Iwakichi, who were shipwrecked apprentice sailors who drifted to Cape Flattery, Washington, USA. They were sent to Macau by John Mclaughlin of the Hudson Bay Company, a British trading firm. The manuscripts were sent to a printing firm in Singapore.
Gutzlaff was the magistrate of Ningbo in 1841 and Zhenjiang in 1842. He helped the EIC to negotiate the Treaty of Nanjing in 1842 and 1843. Gutzlaff then settled in Hong Kong. Forbidden to enter China by the treaty agreements, Gutzlaff formed the Chinese Union in 1844 to employ Chinese evangelists to work in Guangdong. His aim was to have Christian bodies or unions (which would be assisted by their counterpart associations in Europe) in every province. He raised enthusiastic support from Germany through his voluminous writings, but in China, to his disappointment, Gutzlaff discovered that many of the Chinese preachers were unconverted opium-smokers and criminals who had duped him by selling the evangelistic literature to the printer, who then resold it to Gutzlaff.
Gutzlaff died in Hong Kong at age 48 before he could correct the situation, but he was instrumental in attracting other German missionaries to China. His writings on China included the two-volume work Sketch of Chinese History and China Opened.