PROFILE Profile of Shinya Yamanaka ore than a decade ago, Shinya Yamanaka gazed through Ma microscope at human em- bryos growing in a laboratory dish at a fertility clinic in Osaka, Japan. The pulsating blobs struck a primitive chord in the young researcher. “Watching the embryos, I felt that if there was a way to find cures for human diseases without destroying them, then that’swhatIshould pursue,” recalls Yamanaka, a stem cell biologist at Japan’s Kyoto University and a newly elected foreign associate of the National Academy of Sciences. That close encounter with a kernel of human life led to ascientific exploration with a societal un- dertow. Years later, Yamanaka discovered a genetic recipe that allows researchers to bypass the use of human embryos to create Shinya Yamanaka. a range of cell types implicated in diseases. His magic ingredients? A quartet of gene signed up for doctoral studies in phar- biology. At Gladstone, the duo engineered switches that could help turn adult human cells into an embryo-like state, leading to macology at Osaka City University an enzyme into the liver cells of mice disease models, drug tests, and, someday, Graduate School of Medicine in 1989, to lower the levels of apolipoprotein B, even replacements for diseased human tis- upon the suggestion of senior physician a biochemical precursor of bad cholesterol ’ Mamoru Okubo. At Osaka City Univer- that can cause diseases like atherosclero- sues. Today, Yamanaka s accomplishment ’ is acclaimed as nearly unmatched in its sity he designed, performed, and in- sis. To the researchers puzzlement, the impact on regenerative medicine. terpreted experiments, all while attending transgenic mice sprouted liver tumors, In Osaka, a bustling commercial hub and to patients. Under the tutelage of phar- suggesting that overproducing the enzyme macologists Kenjiro Yamamoto and could trigger cancer. Yamanaka reported home to electronics giants like Panasonic fi and Sanyo, Yamanaka was born to parents Katsuyuki Miura, he examined the role of those ndings in a 1995 PNAS paper, who manufactured spare parts for sewing a lipid named platelet-activating factor in following up 2 years later with a partial machines. When he was 10 his family lowering blood pressure in dogs. The explanation for the unexpected outcome fi moved east to Nara, where iconic temples ndings, published in a 1992 issue of (2, 3). The enzyme, it turned out, also al- Circulation Research bear witness to a Buddhist landscape. From , made plain the lip- tered the levels of another protein named ’ an early age, Yamanaka’s father motivated id s mechanism of action: platelet-acti- Nat1, whose function remained a mystery. him to pursue a career in medicine instead vating factor, he found, triggers the Probing deeper, Yamanaka set to work on of enlisting him in the family enterprise. synthesis of a hormone-like molecule a knockout mouse for Nat1, as he isolated, Add to his father’sinfluence a childhood called prostacyclin, which dilates blood cultured, and engineered mouse embry- spent recovering from sports injuries, and vessels and lowers blood pressure (1). onic stem cells. But he returned to Osaka Yamanaka’s choice of a career in ortho- In 1992, when transgenic technology was before he could solve the mystery of Nat1. pedic surgery seemed cast in stone. “I stretching the limits of possibility for mo- “I wanted to stay on in the United States suffered from bone fractures more than 10 lecular biologists, Yamanaka graduated forever, but my wife wanted a Japanese times from playing judo in school. I went with a PhD in pharmacology. In the wake elementary school education for my to orthopedic clinics so often, it was nat- of biochemist Mario Capecchi’s Nobel daughters,” he recalls. ural for me to be interested in orthopedic Prize-winning discovery that among the Those initial efforts at Gladstone her- surgery,” he says. In 1981 he joined Kobe tens of thousands of then-known mam- alded coming discoveries in stem cell bi- University School of Medicine, working malian genes, individual genes could be ology. Back at Osaka City University, toward his chosen specialty, which he be- singled out for silencing to create so- where he was hired as an assistant pro- gan practicing upon graduation. While at called “knockout” mice, Yamanaka be- fessor with the support of pharmacologist Kobe University, he completed a 3-month came interested in transgenic technology Hiroshi Iwao, Yamanaka found that the laboratory stint in forensic medicine, using as a way to probe the function of genes protein Nat1 shepherded mouse embry- mass spectrometry to investigate aspects in mammalian cells. Determined to work onic stem cells in their developmental of alcohol metabolism in people. The ex- in the United States, where the techno- pathway. There, he studied how the cells perience ignited his interest in laboratory logy originated, he sent off dozens of differentiate into adult cells, as his interest science, one that he has kept up with letters seeking a postdoctoral position in in them deepened, he wrote in a Nature a career-defining drive. molecular genetics, hoping to beat the Medicine commentary, from “research seemingly insurmountable odds facing tool to research subject” (4). From Surgery to Stem Cells a surgeon-researcher with scant experi- Yet the tepid response to his basic re- During his residency, Yamanaka began to ence in genetics. search subject at Osaka City University’s have doubts about his calling; he reckoned It was the willingness of University of medical school made him yearn for the that surgery, no matter how lifesaving, California, San Francisco (UCSF) genet- vivifying ferment of American research cannot solve medicine’s abiding mysteries. icist Thomas Innerarity at the Gladstone settings. Fortunately, an associate pro- Nor was he cut out, he realized, for the Institute of Cardiovascular Disease that fessorship in 1999 at Nara Institute of sedulous craft of surgery. As a result, he led to Yamanaka’s break in molecular Science and Technology, where he was www.pnas.org/cgi/doi/10.1073/pnas.1121498109 PNAS Early Edition | 1of3 Downloaded by guest on October 1, 2021 charged with establishing a knockout the field of stem cell biology, Yamanaka mouse facility, satisfied his yearning. “The shared the 2009 Lasker Basic Medical scientific environment at the institute in Research Award with Gurdon, an ac- Nara was very important to my career,” complishment whose singular nature is Yamanaka says. underscored by the years that separate the researchers’ careers. “Sir John Gur- Anchored in History don performed his experiment in nuclear Yamanaka’s work in stem cell biology reprogramming in 1962; that’s when I was harks back to the 1998 isolation of human born. It is a tremendous honor to share embryonic stem cells by University of the award with him,” Yamanaka explains. Wisconsin stem cell biologist James Thomson. The technical feat followed that Riding an Obstacle Course of British Nobelist Martin Evans, who, in But the technique’s shortfalls soon di- the early 1980s, devised a way to grow minished its promise. One of the gene entire mice from mouse embryonic switches Yamanaka used to induce plu- stem cells. Hailed as a breakthrough, ripotency can lead to cancer, which the Thomson’s discovery pointed to a wealth Dopaminergic neurons derived from human iPS switch promptly triggered in some animal cells. of potential medical applications for stem experiments. Moreover, the retrovirus cells. Because stem cells in the embryo are used to ferry the switches into adult hu- a sort of developmental blank slate, they turn adult mouse cells into a state called man cells can slip into chromosomes and can be prodded to adopt specific fates—to pluripotent, enabling them to further sabotage gene regulation, also leading to turn into adult muscle, heart, liver, brain, morph into many cell types. “It took us cancer. To further complicate matters, and other cell types—with combinations almost 5 years to identify those candi- stem cells derived through the technique of chemicals and conditions. Researchers dates,” Yamanaka recalls. Meanwhile, were not always identical to embryonic can use adult cells derived from embry- Thomson’s isolation of human embryonic stem cells; subtle differences came to onic stem cells to learn what goes awry in stem cells meant that Yamanaka could light when the cells were induced to adopt certain diseases, to test candidate drugs move the field’s frontiers by replicating specific fates. Some researchers reported for those diseases, and to potentially cre- those findings in human cells; the em- mutations that seemed to have arisen ate a pipeline of replacement parts for bryonic stem cells would serve as a through reprogramming. Others found diseased tissues. But ethical concerns benchmark. “But the institute in Nara that induced pluripotent stem cells re- surrounding embryonic stem cell research does not have a medical school or hos- tained a memory of their adult cell of have mired the field in controversy; stem pital, so getting human embryonic stem origin, resisting attempts to turn them cells are typically extracted by destroying cells was difficult,” Yamanaka recalls. into a different type of adult cell. Which is human embryos that fertility clinics often That is partly why he accepted a pro- partly why, Yamanaka says, the need discard. At Nara, Yamanaka developed fessorship at the Institute of Frontier for research on human embryonic stem a workaround by upending a logic un- Medical Sciences at Kyoto University, cells remains as pressing as ever—to derlying regenerative medicine. He found where at first he whittled down his list of provide researchers with a standard for a way to turn adult cells into an embryo- 24 gene switches to no more than four, comparison. like state, establishing what could be namely Oct3/4, Sox2, Klf4, and c-Myc— But the field suffered a setback in 2010 a wellspring of cell types.