is a Japanese stem cell researcher and a Nobel Prize laureate.
He is a professor and the director emeritus of the Center for iPS Cell (induced Pluripotent Stem Cell) Research and Application, Kyoto University; as well as a senior investigator at the UCSF-affiliated Gladstone Institutes in San Francisco, California, and a professor of anatomy at the University of California, San Francisco (UCSF). Yamanaka is also a past president of the International Society for Stem Cell Research (ISSCR).
He received the 2010 BBVA Foundation Frontiers of Knowledge Award in the biomedicine category, the 2011 Wolf Prize in Medicine with Rudolf Jaenisch, and the 2012 Millennium Technology Prize together with Linus Torvalds.
In 2012, he and John Gurdon were awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells. In 2013, he was awarded the $3 million Breakthrough Prize in Life Sciences for his work.
Education Yamanaka was born in Higashiōsaka, Japan, in 1962. After graduating from Tennōji High School attached to Osaka Kyoiku University, he received his M.D. degree at Kobe University in 1987 and his Ph.D. degree at Osaka City University, Graduate School of Medicine in 1993. After this, he went through a residency in orthopedic surgery at National Osaka Hospital and a postdoctoral fellowship at the Gladstone Institute of Cardiovascular disease, San Francisco.
Afterwards, he worked at the Gladstone Institutes in San Francisco, US, and Nara Institute of Science and Technology in Japan. Yamanaka is currently a professor and the director emeritus of Center for iPS Research and Application (CiRA), Kyoto University. He is also a senior investigator at the Gladstone Institutes.
Professional career Between 1987 and 1989, Yamanaka was a resident in orthopedic surgery at the National Osaka Hospital. Some seniors referred to him as "Jamanaka", a pun on the Japanese word for obstacle.The Asahi Shimbun After failure as a surgeon, Yamanaka rises to stem cell glory October 9, 2012
From 1993 to 1996, he was at the Gladstone Institute of Cardiovascular disease. 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.
When applying for a position at the Nara Institute of Science and Technology (NAIST), 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 to 2003, he was an associate professor at the institute, and began the research that would later win him the 2012 Nobel Prize. He became a full professor at NAIST in 2003, remaining until 2005. Between 2004 and 2010, Yamanaka was a professor at the Institute for Frontier Medical Sciences, Kyoto University. Between 2010 and 2022, he was the director and a professor at the center for iPS Cell Research and Application (CiRA), Kyoto University. In April 2022, he stepped down, becoming director emeritus of CiRA, while retaining his professorship.
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 four transcription factors – Sox2, Oct4, Klf4 and c-Myc.
20 years later, the Ministry of Health, Labor and Welfare in Japan issued conditional marketing authorization in 2026 to two regenerative medical products developed from reprogrammed iPS cells, undertaking the first ever practical application of iPS cell-derived products.
Nobel Prize for iPS cell research The 2012 Nobel Prize in Physiology or Medicine was awarded jointly to Yamanaka and John B. Gurdon and "for the discovery that mature cells can be reprogrammed to become pluripotent."
The Center for iPS Cell Research and Application (CiRA) at Kyoto University responded to allegations of image manipulation in several studies co-authored by Nobel laureate Shinya Yamanaka. CiRA stated that questioning Yamanaka's integrity without sufficient evidence was “completely unacceptable.”
Background-different cell types There are different types of stem cells. These are some types of cells that will help in understanding the material. Cell types Characteristics Totipotent cells Can give rise to all other cell types. Totipotency remains through the first few cell divisions, e.g. the fertilised egg. Pluripotent cells Can develop into all cell types (except those that form the amniotic sac and the placenta). For example, the early embryo consists mainly of pluripotent stem cells. Multipotent cells Can develop into any of a family of closely related cell types. For example, blood multipotent cells can develop into various blood cells.
Background-different stem cell techniques Type Pros Cons Somatic cell replication Embryonic Stem (ES) cell No immune rejection Theoretically patient-specific transplantations possible No case of successMany human egg cells neededEthical issue: Can clone humans Fertilized egg ES cell Pluripotent Much research done
Immune rejection reducible via stem cell bank Fertilized egg usageImmune rejectionOncogenic potential(can't use for clinical trial) Induced pluripotent stem (iPS) Cell No ethical issue Pluripotent Oncogenic potential Abnormal aging Adult stem cell Much research No immune rejection Safe (clinical trials) Not as much differentiation potential as ES cell
Historical background
The prevalent view during the early 20th century was that mature cells were permanently locked into the differentiated state and cannot return to a fully immature, pluripotent stem cell state. It was thought that cellular differentiation can only be a unidirectional process. Therefore, non-differentiated egg/early embryo cells can only develop into specialized cells. However, stem cells with limited potency (adult stem cells) remain in bone marrow, intestine, skin etc. to act as a source of cell replacement.
The fact that differentiated cell types had specific patterns of proteins suggested irreversible epigenetic modifications or genetic alterations to be the cause of unidirectional cell differentiation. So, cells progressively become more restricted in the differentiation potential and eventually lose pluripotency.
In 1962, John B. Gurdon demonstrated that the nucleus from a differentiated frog intestinal epithelial cell can generate a fully functional tadpole via transplantation to an enucleated egg. Gurdon used somatic cell nuclear transfer (SCNT) as a method to understand reprogramming and how cells change in specialization. He concluded that differentiated somatic cell nuclei had the potential to revert to pluripotency. This was a paradigm shift at the time. It showed that a differentiated cell nucleus has retained the capacity to successfully revert to an undifferentiated state, with the potential to restart development (pluripotent capacity).
Whether an intact differentiated cell could be fully reprogrammed to become pluripotent remained unknown.
Yamanaka's research Shinya Yamanaka found that introduction of a small set of transcription factors into a differentiated cell was sufficient to revert the cell to a pluripotent state. Yamanaka focused on factors that are important for maintaining pluripotency in embryonic stem (ES) cells. This was the first time an intact differentiated somatic cell could be reprogrammed to become pluripotent.
Knowing that transcription factors were involved in the maintenance of the pluripotent state, he selected a set of 24 ES cell transcriptional factors as candidates to reinstate pluripotency in somatic cells. First, he collected the 24 candidate factors. When all 24 genes encoding these transcription factors were introduced into skin fibroblasts, few actually generated colonies that were remarkably similar to ES cells.
Secondly, further experiments were conducted with smaller numbers of transcription factors added to identify the key factors, through a very simple and yet sensitive assay system. Lastly, he identified the four key genes. They found that four transcriptional factors (Myc, Oct3/4, Sox2 and Klf4) were sufficient to convert mouse embryonic or adult fibroblasts to pluripotent stem cells (capable of producing teratomas in vivo and contributing to chimeric mice).
These pluripotent cells are called iPS (induced pluripotent stem) cells; they appeared with very low frequency. iPS cells can be selected by inserting the b-geo gene into the Fbx15 locus. The Fbx15 promoter is active in pluripotent stem cells which induce b-geo expression, which in turn gives rise to G418 resistance; this resistance helps us identify the iPS cells in culture.
In 2007, Yamanaka and his colleagues found iPS cells with germline transmission (via selecting for Oct4 or Nanog gene). Also in 2007, they were the first to produce human iPS cells.
Some issues that current methods of induced pluripotency face are the very low production rate of iPS cells and the fact that the 4 transcriptional factors are shown to be oncogenic.
In July 2014, during a scandal involving Japanese stem cell researcher Haruko Obokata fabricating data, doctoring images, and plagiarizing the work of others, Yamanaka faced public scrutiny for his associated work lacking full documentation. Yamanaka denied manipulating images in his papers on embryonic mouse stem cells, but he could not find lab notes to confirm that the raw data was consistent with the published results.
Further research and future prospects Since the original discovery by Yamanaka, much further research has been done in this field, and many improvements have been made to the technology. Improvements made to Yamanaka's research as well as future prospects of his findings are as follows:
The delivery mechanism of pluripotency factors has been improved. At first retroviral vectors, that integrate randomly in the genome and cause deregulation of genes that contribute to tumor formation, were used. However, now, non-integrating viruses, stabilised RNAs or proteins, or episomal plasmids (integration-free delivery mechanism) are used. Transcription factors required for inducing pluripotency in different cell types have been identified (e.g. neural stem cells). Small substitutive molecules were identified, that can substitute for the function of the transcription factors. Transdifferentiation experiments were carried out. They tried to change the cell fate without proceeding through a pluripotent state. They were able to systematically identify genes that carry out transdifferentiation using combinations of transcription factors that induce cell fate switches. They found transdifferentiation within germ layer and between germ layers, e.g., exocrine cells to endocrine cells, fibroblast cells to myoblast cells, fibroblast cells to cardiomyocyte cells, fibroblast cells to neurons