Biography: Shinya Yamanaka
Embryonic Stem Cell Research

Shinya Yamanaka was born in Osaka, Japan, where his father owned a small factory. Surrounded by machinery, young Shinya developed an enthusiasm for all technical subjects. In school, he was drawn to science; he was also an enthusiastic athlete. His passion for judo resulted in a number of broken bones and frequent visits to the orthopedist. Although he ultimately earned a black belt in judo, these experiences also awakened his interest in medicine.

After graduating from a high school attached to the university in Osaka, he earned a medical degree at Kobe University. He completed a residency in orthopedic surgery at National Osaka Hospital, but became frustrated with his lack of dexterity as a surgeon. He decided to pursue a career in research instead, and enrolled at Osaka University, earning a Ph.D. in pharmacology.

In graduate school, a chance reading of a paper on genetically engineered mice, so-called "knockout mice," led him to the study of gene replacement. By eliminating individual genes from the mouse genome, scientists were able to learn the function of each gene. Yamanaka was eager to work with this new technology, but there were no institutions pursuing this research in Japan. He wrote to 30 universities and laboratories in the United States, searching for a postdoctoral fellowship in the field, before finding a place at the University of California, San Francisco.

Yamanaka was thrilled with the research opportunities he enjoyed in the United States. When he was offered an assistant professorship at Osaka, he returned to Japan with a cage full of genetically engineered mice for experimentation. Unfortunately, he lacked the staff to do much more than look after his research animals, without pursuing any new projects. By this time, Yamanaka had married and started a family, but his professional life was stalled. His situation at Osaka was especially disappointing because he was eager to apply knockout mouse technology to the newly emerging field of stem cell research.

Stem cells are the undifferentiated cells found in the embryos of all animals. As the embryonic creature gestates, these cells differentiate, becoming the cells that make up bone, blood, nerves and other tissues. At the close of the 20th century, stem cell research in both Japan and the United States was encumbered with a major ethical controversy. The best sources of human stem cells were the embryos discarded by fertility clinics, but destroying human embryos for research purposes struck government leaders in both countries as morally unacceptable. In 2001, U.S. President George W. Bush explicitly barred federal funding for any research involving the creation of new stem cell lines from human embryos. In Japan, the rules regarding research with embryonic tissue were even more stringent. Yamanaka considered the possibility that the cells of an adult animal could be reprogrammed to their embryonic, pluripotent state.

Frustrated with his lack of support at Osaka, Yamanaka considered returning to medical practice, when the opportunity arose to lead his own laboratory at another university in nearby Nara. He knew that if his new laboratory were to thrive, he would need to attract first-rate graduate students and postdoctoral fellows with a unique and intriguing research project. One day, while visiting a friend's fertility clinic, Dr. Yamanaka found himself gazing at human embryos through a microscope and became convinced that an alternative to the use of embryonic tissue in stem cell research must be found. While most contemporary stem cell research involved controlling the process by which the stem cells differentiated into other cell types, Yamanaka decided he would pursue the opposite course, reprogramming the cells of an adult animal to return to their embryonic pluripotent state.

The idea seemed improbable to most of his peers, and the chances of success marginal, but the idea was so unusual, his lab attracted exceptionally talented students. Identifying the combination of genes that would convert adult cells back into their pluripotent state could require testing hundreds of possible combinations, the work of decades. Working 12 to 16 hours a day for months on end, Yamanaka reviewed the existing literature, and tried to identify the most promising combinations. Balancing meticulous research with informed intuition, he compiled a list of the 24 most likely combinations, and decided to test those first. In 2006, only five years into his project, he found a combination of four genes that converted the skin cells of an adult mouse back to their pluripotent state. His hunch had paid off, saving his team years of work.

The news of Dr. Yamanaka's discovery, quickly confirmed by other laboratories working independently, spread like wildfire through the scientific world. Everywhere, the same question sprang to mind. Would Yamanaka's technique work with human cells as well as those of mice? An additional concern arose. Of the four gene combinations Yamanaka had used, two have been implicated in cancer. One of these has a relatively weak statistical relationship with cancer, but the other, c-Myc, is a well-known cancer gene.

Repeating the process with human cells posed additional difficulties, including the possibility of an increased risk for cancer, but Yamanaka had become adept at overcoming difficulties and accomplishing his research goals at record speed. Within a year, Yamanaka had duplicated the results with human cells. In the process, he learned that c-Myc could be omitted from the combination, generating the same results with a greatly decreased risk of cancer. His accomplishment was recognized with honors from governments around the world, including the Osaka Science Prize in Japan, and the Lasker Award in the United States. In 2012 he received the Nobel Prize in Medicine.

Dr. Yamanaka now divides his time between professorships at Kyoto University and the University of California's Gladstone Institutes in San Francisco. A vigorous and athletic man, he continues to work long days, relishes his scientific pursuits and peppers his conversation with jokes in a way that his colleagues find more American than Japanese. Still an enthusiastic athlete, he enjoys a brisk run or swim between marathon sessions in the laboratory.