Between 1987 and 1989, Yamanaka was a resident in orthopedic surgery at the National Osaka Hospital. His first operation, was removing a benign tumor from his friend Shuichi Hirata, a task he could not complete after one hour, when a skilled surgeon would take ten minutes or so. Some seniors referred to him as "Jamanaka", a pun on the Japanese word for obstacle.
From 1993 to 1996, he was at the Gladstone Institute of Cardiovascular Disease, which is affiliated with the University of California, San Francisco, where there was an atmosphere of freedom and the ability to speak frankly with colleagues. Between 1996 and 1999, he was an assistant professor at Osaka City University Medical School, but found himself mostly looking after mice in the laboratory, not doing actual research.
His wife advised him to become a practicing doctor, but instead he applied for a position at the Nara Institute of Science and Technology. He stated that he could and would clarify the characteristics of embryonic stem cells, and this can-do attitude won him the job. From 1999–2003, he was an associate professor there, and started the research that would later win him the 2012 Nobel Prize. He became a full professor and remained at the institute in that position from 2003–2005. Between 2004 and 2010, Yamanaka was a professor at the Institute for Frontier Medical Sciences. Currently, Yamanaka is the director and a professor at the Center for iPS Cell Research and Application at Kyoto University.
In 2006, he and his team generated induced pluripotent stem cells (iPS cells) from adult mouse fibroblasts. iPS cells closely resemble embryonic stem cells, the in vitro equivalent of the part of the blastocyst (the embryo a few days after fertilization) which grows to become the embryo proper. They could show that his iPS cells were pluripotent, i.e. capable of generating all cell lineages of the body. Later he and his team generated iPS cells from human adult fibroblasts, again as the first group to do so. A key difference from previous attempts by the field was his team's use of multiple transcription factors, instead of transfecting one transcription factor per experiment. They started with 24 transcription factors known to be important in the early embryo, but could in the end reduce it to 4 transcription factors – Sox2, Oct4, Klf4 and c-Myc.
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