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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 biologist at Japan’s 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 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 ’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 , 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 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 , 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 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 , 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 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, , , and c-— But the field suffered a setback in 2010 a wellspring of cell types. genes with near-magical ability to reset when a federal judge in Washington, DC Yamanaka’s workaround is rooted in the developmental clock in mouse cells. blocked President Obama’s efforts to ex- the history of regenerative biology, That landmark 2006 discovery announced pand human embryonic stem cell re- marked by a 1962 milestone discovery by the advent of stem cell technology in the search beyond the small number of biologist Sir pages of Cell (5). A year later, Yamanaka previously established cell lines on the , who created frogs in the and Thomson separately demonstrated grounds that federal money could not be laboratory by transplanting the nucleus of the transformation of adult human skin used to destroy human embryos for re- a tadpole’s fully developed intestinal cell cells—removed from the face or foreskin search. As federally funded stem cell re- into the enucleated egg cell of an African —into an embryonic state. Those findings searchers in the United States grappled clawed toad. More than three decades are widely regarded as the bedrock of with a brief moratorium, scrambling to later, nuclear transplantation moved into today’s stem cell biology (6, 7). save their experiments, the decision— the mainstream when British embryolo- Soon thereafter, reports from other overturned on appeal a year later—raised gist gave the world its first researchers trickled in, demonstrating the the temperature of a long-simmering cloned sheep, . From Gurdon’s frogs conversion of adult human cells into debate over stem cells. Yamanaka’s to Wilmut’s sheep, researchers had long a range of cell types—heart cells, brain stance toward the ethical conundrum suspected the existence of mysterious cells, and pancreatic cells—affected in surrounding stem cells is categorical: “My factors in egg cells that reprogrammed conditions like cardiovascular disease, position has always been that if we can the nucleus of an adult cell to an embry- Parkinson’s disease, and diabetes. The avoid using human embryos we should. onic state. But the factors remained elu- cells helped researchers test the safety At the moment, we are not 100% sure sive until Yamanaka began to look for his and efficacy of drugs against those dis- that human-induced pluripotent stem workaround in the late 1990s. eases in Petri dishes, and even develop cells are equivalent to human embryonic Though Yamanaka is best known for his models for those diseases. Because cells stem cells. To confirm that, we have to technique to bypass the use of embryos in derived from a patient’s own cells can be use several human embryonic stem cell stem cell research, the reason behind his transplanted into the patient for thera- lines. Without any question, human em- rise to scientific prominence is his insight peutic purposes someday, Yamanaka’s bryonic stem cell research is crucial.” into the nature and transferability of those method can potentially sidestep adverse Following that line of reasoning, fate-changing factors in embryonic cells. immune reactions triggered by trans- Yamanaka continues to work on human With his team at the Nara Institute, he planting cells derived from an embryo. embryonic stem cells in Kyoto, traveling homed in on 24 gene switches that could For findings that solidified his position in every month to San Francisco, where

2of3 | www.pnas.org/cgi/doi/10.1073/pnas.1121498109 Nair Downloaded by guest on October 1, 2021 he holds appointments at Gladstone and a few may be around the corner. For ex- planted into genetically identical mice, UCSF. Over the years, he has honed his ample, a team at Stanford University led suggesting that the manner in which plu- technique to address some of its short- by dermatologist Alfred Lane is exploring ripotency is induced might influence im- comings. In 2007, he reported that the the use of induced pluripotent stem cells mune rejection in patients. Reports of technique worked even when the cancer- to replace damaged skin cells in people incomplete or insufficient reprogramming causing Myc gene switch was left out of his afflicted with a rare genetic disorder often baffle stem cell researchers. But reprogramming recipe (8). The following called epidermolysis bullosa, which causes Yamanaka counters that the findings on year, his team reported a technique to in- skin to slough off upon physical stress. immunogenicity are far from conclusive duce pluripotency in mouse cells without The US Food and Drug Administration and that such problems may be sur- using a viral ferry; the switches were carried has greenlighted Massachusetts-based mounted in the near future, raising fresh aboard DNA circles called plasmids that biotechnology firm Advanced Cell Tech- hope for the technology’s promise to help deliver their cargo without inserting them- nology’s phase II trial of adult stem cell treat human diseases. “The main hurdle selves into the cells’ genomes, thus re- therapy for patients in the late stages of is safety associated with the use of induced ducing the risk of cancer (9). And in 2011 congestive heart failure without recourse pluripotent stem cells in people,” he adds. he described a way to generate human to heart transplants. And researchers Recognizing the technology’s potential, pluripotent cells without using viruses (10). at Japan’s renowned RIKEN Center despite the roadblocks facing the clinical Meanwhile, other researchers have for Developmental Biology in Kobe, application of stem cells, Japan’s Inamori put Yamanaka’s technique to promising Yamanaka says, have generated human Foundation awarded the 2010 Kyoto preclinical use. Harvard University stem retinal pigment epithelial cells from in- Prize in Advanced Technology to Yama- cell biologist Douglas Melton successfully duced pluripotent stem cells. The RIKEN naka. Dismissing widespread speculation treated diabetic mice with insulin-secret- group, he adds, hopes to begin a clinical of his odds of winning science’s most — ing pancreatic beta cells normally de- trial of a treatment for age-related mac- coveted prize in the not-so-distant future, — stroyed by diabetes derived from ular degeneration, a leading cause of Yamanaka says, “The technology is another type of pancreatic cell. Molecular blindness among millions of people still very young. Ten years from now, we biologist Bruce Spiegelman at the Dana- worldwide. hope to have created an effective treat- Farber Cancer Institute turned harmful As research on induced pluripotent fi fi ment using patient-speci c, iPS cell- white fat cells, which can cause obesity, stem cells advances, the eld faces fresh derived cells. We also hope that the into calorie-burning brown fat cells. challenges. In May 2011, researchers at technology will lead to clinical trials for the University of California, San Diego diseases like Parkinson’s and macular Shadow over Promise reported that induced pluripotent stem degeneration.” Though treatments based on Yamanaka’s cells derived from the skin cells of mice technique have yet to reach the clinic, suffered immune rejection when im- Prashant Nair, Science Writer

1. Yamanaka S, Miura K, Yukimura T, Okumura M, transgene expression of the apoB mRNA-editing en- 7. Yu J, et al. (2007) Induced pluripotent stem cell lines de- Yamamoto K (1992) Putative mechanism of hypoten- zyme. Genes Dev 11:321–333. rived from human somatic cells. Science 318:1917–1920. sive action of platelet-activating factor in dogs. Circ 4. Yamanaka S (2009) Ekiden to iPS Cells. Nat Med 15: 8. Nakagawa M, et al. (2008) Generation of induced Res 70:893–901. 1145–1148. pluripotent stem cells without Myc from mouse and 2. Yamanaka S, et al. (1995) Apolipoprotein B mRNA- 5. Takahashi K, Yamanaka S (2006) Induction of plu- human fibroblasts. Nat Biotechnol 26:101–106. editing protein induces hepatocellular carcinoma and ripotent stem cells from mouse embryonic and adult 9.OkitaK,NakagawaM,HyenjongH,IchisakaT, dysplasia in transgenic animals. Proc Natl Acad Sci USA fibroblast cultures by defined factors. Cell 126: Yamanaka S (2008) Generation of mouse induced plurip- 92:8483–8487. 663–676. otent stem cells without viral vectors. Science 322:949–953. 3. Yamanaka S, Poksay KS, Arnold KS, Innerarity TL 6. Takahashi K, et al. (2007) Induction of pluripotent 10. Okita K, et al. (2011) A more efficient method to (1997) A novel translational repressor mRNA is edited stem cells from adult human fibroblasts by defined generate integration-free human iPS cells. Nat Meth- extensively in livers containing tumors caused by the factors. Cell 131:861–872. ods 8:409–412.

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