Shinya Yamanaka

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Shinya Yamanaka
Shinya yamanaka10.jpg
Born (1962-09-04) September 4, 1962 (age 52)
Higashiōsaka, Osaka, Japan
Nationality Japan
Fields Stem cell research[1][2][3]
Institutions Kyoto University
Nara Institute of Science and Technology
Gladstone Institute of Cardiovascular Disease
Alma mater Kobe University
Osaka City University
Known for Induced pluripotent stem cell
Notable awards Meyenburg Prize (2007)
Massry Prize (2008)
Robert Koch Prize (2008)
Shaw Prize (2008)
Gairdner Foundation International Award (2009)
Albert Lasker Basic Medical Research Award (2009)
BBVA Foundation Frontiers of Knowledge Award (2010)
Wolf Prize (2011)
McEwen Award for Innovation (2011)
Fellow of the National Academy of Sciences[4] (2012)
Millennium Technology Prize (2012)
Nobel Prize in Physiology or Medicine (2012)
Video of a single beating cardiomyocyte, taken from an open-access article co-authored by Yamanaka.[5] Isolating cells by cell type is an important step in stem cell therapy.

Shinya Yamanaka (山中 伸弥 Yamanaka Shin'ya?, born September 4, 1962) is a Japanese Nobel Prize-winning stem cell researcher.[1][2][3] He serves as the director of Center for iPS Cell (induced Pluripotent Stem Cell) Research and Application and a professor at the Institute for Frontier Medical Sciences at Kyoto University; as a senior investigator at the UCSF-affiliated J. David Gladstone Institutes in San Francisco, California; and as a professor of anatomy at 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 Biomedicine category. Also he received the Wolf Prize in Medicine in 2011 with Rudolf Jaenisch;[6] the Millennium Technology Prize in 2012 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.[7] In 2013 he was awarded the $3 million Breakthrough Prize in Life Sciences for his work.

Education[edit]

Yamanaka was born in Higashiōsaka Japan in 1962. After graduating from Tennōji High School attached to Osaka Kyoiku University,[8] he received his M.D. at Kobe University in 1987 and his PhD at Osaka City University Graduate School 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, USA and Nara Institute of Science and Technology in Japan. Yamanaka is currently Professor at Kyoto University, where he directs its Center for iPS Research and Application. He is also a senior investigator at the Gladstone Institutes as well as the director of the Center for iPS Cell Research and Application.[9]

Professional career[edit]

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.[10]

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.[10]

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.[11] 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.[1] 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,[2] 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.[1]

Interest in sports[edit]

Yamanaka practiced judo (2dan black belt) and played rugby as a university student. He also has a history of running marathons. After a 20-year gap, he competed in the inaugural Osaka Marathon in 2011 as a charity runner with a time of 4:29:53. He also took part in the 2012 Kyoto Marathon to raise money for iPS research, finishing in 4:03:19. He also ran in the second Osaka Marathon on November 25, 2012.[12]

Recognition[edit]

Shinya Yamanaka speaking at a lecture on January 14, 2010

In 2007, Yamanaka was recognized as a "Person Who Mattered" in the Time Person of the Year edition of Time Magazine.[13] Yamanaka was also nominated as a 2008 Time 100 Finalist.[14] In June 2010, Yamanaka was awarded the Kyoto Prize for reprogramming adult skin cells to pluripotential precursors. Yamanaka developed the method as an alternative to embryonic stem cells, thus circumventing an approach in which embryos would be destroyed.

In May 2010, Yamanaka was given "Doctor of Science honorary degree" by Mount Sinai School of Medicine.[15]

In September 2010, he was awarded the Balzan Prize for his work on biology and stem cells.[16]

Yamanaka has been listed as one of the 15 Asian Scientists To Watch by Asian Scientist magazine on May 15, 2011.[17][18] In June 2011, he was awarded the inaugural McEwen Award for Innovation; he shared the $100,000 prize with Kazutoshi Takahashi, who was the lead author on the paper describing the generation of induced pluripotent stem cells.[19]

In June 2012, he was awarded the Millennium Technology Prize for his work in stem cells.[20] He shared the 1.2 million euro prize with Linus Torvalds, the creator of the Linux kernel.

Nobel Prize[edit]

In October 2012, he and fellow stem cell researcher John Gurdon were awarded the Nobel Prize in Physiology or Medicine "for the discovery that mature cells can be reprogrammed to become pluripotent."[21]

Yamanaka's Nobel Prize–winning research in iPS cells[edit]

The 2012 Nobel Prize in Physiology or Medicine was awarded jointly to Sir John B. Gurdon and Shinya Yamanaka "for the discovery that mature cells can be reprogrammed to become pluripotent."[22]

Background-different cell types[edit]

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 ex. the fertilised egg

Pluripotent cells Can develop into all cell types (except those that form the amniotic sac and the placenta)

The early embryo consists mainly of pluripotent stem cells

Multipotent cells Can develop into any of a family of closely related cell types

ex) blood multipotent cells can develop into various blood cells

Background-different stem cell techniques[edit]

Type Pros Cons
Somatic cell replication Embryonic Stem (ES) cell No immune rejection

Theoretically patient-specific transplantations possible

No case of success
Many human egg cells needed
Ethical issue: Can clone humans
Fertilized egg ES cell Pluripotent

Much research done Immune rejection reducible via stem cell bank

Fertilized egg usage
Immune rejection
Oncogenic 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 potential as ES cell

Historical Background leading up to Yamanaka's research[edit]

The prevalent view during the early 20C was that mature cells were permanently locked into the differentiated state and cannot return to a fully immature, pluripotent stem cell state. They 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.[23]

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.[24]

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 during the time. It showed that a differentiated cell nucleus has retained the capacity to successfully revert to an undifferentiated state, with a potential to restart development (pluripotent capacity).

However, the question still remained whether an intact differentiated cell could be fully reprogrammed to become pluripotent. Shinya Yamanaka proved that introduction of a small set of transcription factors into a differentiated cell was sufficient to revert the cell to a pluripotent state.

Yamanaka's research[edit]

Shinya Yamanaka proved 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. 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 factors. They found that 4 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 a culture.

Moreover, in 2007, Yamanaka and his colleagues found iPS cells with germ line transmission (via selecting for Oct4 or Nanog gene). Also in 2007, they were the first to produce human iPS cells.

However, there are some difficulties to overcome. The first is the issue of the very low production rate of iPS cells, and the other is the fact that the 4 transcriptional factors are shown to be oncogenic.

Nonetheless, this is a truly fundamental discovery. This was the first time an intact differentiated somatic cell could be reprogrammed to become pluripotent. This opened up a completely new research field.

In July 2014, a scandal regarding the research of Haruko Obokata was connected to Yamanaka. He could not find the lab notes from the period in question [25] and was made to apologise.[26][27]

Further research and future prospects[edit]

Since the original discovery by Yamanaka, much further research has been done in this field, and many improvements have been made to the technology. Here we discuss the improvements made to Yamanaka's research as well as the future prospects of his findings.

1. 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. 2. Transcription factors required for inducing pluripotency in different cell types have been identified (e.g. neural stem cells). 3. Small substitutive molecules were identified, that can substitute for the function of the transcription factors. 4. 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 trandifferentiation 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 5. Cell replacement therapy with iPS cells is a possibility. Stem cells can replace diseased or lost cells in degenerative disorders and they are less prone to immune rejection. However, there is a danger that it may introduce mutations or other genomic abnormalities that render it unsuitable for cell therapy. So, there are still many challenges, but it is a very exciting and promising research area. Further work is required to guarantee safety for patients. 6. Can medically use iPS cells from patients with genetic and other disorders to gain insights into the disease process. - Amyotrophic lateral sclerosis (ALS), Rett syndrome, spinal muscular atrophy (SMA), α1-antitrypsin deficiency, familial hypercholesterolemia and glycogen storage disease type 1A. - For cardiovascular disease, Timothy syndrome, LEOPARD syndrome, type 1 and 2 long QT syndrome - Alzheimer’s, Spinocerebellar ataxia, Huntington’s etc. 7. iPS cells provide screening platforms for development and validation of therapeutic compounds. For example, kinetin was a novel compound found in iPS cells from familial dysautonomia and beta blockers & ion channel blockers for long QT syndrome were identified with iPS cells.

Yamanaka's research has “opened a new door and the world’s scientists have set forth on a long journey of exploration, hoping to find our cells’ true potential.”[28]

Honors[edit]

References[edit]

General references:

Specific citations:

  1. ^ a b c d Takahashi, K.; Yamanaka, S. (2006). "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors". Cell 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. PMID 16904174.  edit
  2. ^ a b c Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. (2007). "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors". Cell 131 (5): 861–872. doi:10.1016/j.cell.2007.11.019. PMID 18035408.  edit
  3. ^ a b Okita, K.; Ichisaka, T.; Yamanaka, S. (2007). "Generation of germline-competent induced pluripotent stem cells". Nature 448 (7151): 313–317. doi:10.1038/nature05934. PMID 17554338.  edit
  4. ^ a b Nair, P. (2012). "Profile of Shinya Yamanaka". Proceedings of the National Academy of Sciences 109 (24): 9223–9225. doi:10.1073/pnas.1121498109. PMC 3386100. PMID 22619323.  edit
  5. ^ Uosaki, H.; Fukushima, H.; Takeuchi, A.; Matsuoka, S.; Nakatsuji, N.; Yamanaka, S.; Yamashita, J. K. (2011). Prosper, Felipe, ed. "Efficient and Scalable Purification of Cardiomyocytes from Human Embryonic and Induced Pluripotent Stem Cells by VCAM1 Surface Expression". PLoS ONE 6 (8): e23657. doi:10.1371/journal.pone.0023657. PMC 3158088. PMID 21876760.  edit
  6. ^ "Shinya Yamanaka Winner of Wolf Prize in Medicine – 2011". Wolf Foundation. 
  7. ^ "The Nobel Prize in Physiology or Medicine – 2012 Press Release". Nobel Media AB. 8 October 2012. 
  8. ^ http://english.kyodonews.jp/photos/2012/10/186903.html
  9. ^ "The 2012 Nobel Prize in Physiology or Medicine - Press Release". Nobelprize.org. Nobel Media AB 2013. Web. 28 Nov 2013. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html>
  10. ^ a b Asahi Shimbun After failure as a surgeon, Yamanaka rises to stem cell glory October 9, 2012
  11. ^ "Shinya Yamanaka MD., PhD". Kyoto University. Archived from the original on February 10, 2008. 
  12. ^ Daily Yomiuri Yamanaka avid lifelong athlete / Nobel laureate gave same dedication to sports as he has to science October 10, 2012
  13. ^ "Junying Yu, James Thomson and Shinya Yamanaka". Time. December 19, 2007. Retrieved May 23, 2010. 
  14. ^ "Shinya Yamanaka – The 2008 Time 100 Finalists". April 1, 2008. Retrieved May 23, 2010. 
  15. ^ "Mount Sinai School of Medicine Commencement Honors Leaders in Genetics and Public Health". Mount Sinai Hospital, New York. Retrieved 16 August 2013. 
  16. ^ Balzan Prize winners in 2010, from the website of the Fondazione internazionale Premio Balzan
  17. ^ "The Ultimate List Of 15 Asian Scientists To Watch – Shinya Yamanaka". AsianScientist.com. May 15, 2011. Retrieved June 6, 2011. 
  18. ^ Baker, M. (2007). "A Conversation with Shinya Yamanaka, Professor at Kyoto University". Nature Reports Stem Cells. doi:10.1038/stemcells.2007.9.  edit
  19. ^ "McEwen Award for Innovation". ISSCR. Retrieved 2012-10-09. 
  20. ^ Stem cell scientist wins millennium technology prize. BBC.co.uk (June 13, 2012). Retrieved on 2012-10-08.
  21. ^ a b "The Nobel Prize in Physiology or Medicine 2012". NobelPrize.org. October 8, 2012. Retrieved October 8, 2012. 
  22. ^ Nobel Prize in Physiology or Medicine 2012. Nobelprize.org. Nobel Media AB 2013. Web. 28 Nov 2013.
  23. ^ "The 2012 Nobel Prize in Physiology or Medicine - Advanced Information". Nobelprize.org. Nobel Media AB 2013. Web. 29 Nov 2013. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/advanced.html>
  24. ^ "The 2012 Nobel Prize in Physiology or Medicine - Popular Information". Nobelprize.org. Nobel Media AB 2013. Web. 28 Nov 2013. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/popular.html>
  25. ^ http://www.nytimes.com/2014/07/07/world/asia/academic-scandal-shakes-japan.html
  26. ^ http://blogs.wsj.com/japanrealtime/2014/04/28/japanese-nobel-winner-latest-to-apologize-over-stem-cell-research/
  27. ^ http://www.economist.com/blogs/banyan/2014/07/regenerative-medicine
  28. ^ Danielsson, Ola (December 2012). "The Nobel Prize in Physiology or Medicine 2012". p. 7. 
  29. ^ "Meyenburg Cancer Research Award 2007 given to Dr. Shinya Yamanaka for the artificial generation of stem cells". German Cancer Research Center. November 23, 2007. 
  30. ^ "Meyenburg Cancer Research Award 2007 for artificial stem cell production". German Cancer Research Center. November 23, 2007. 
  31. ^ Tucker, Valerie (June 11, 2008). "Gladstone's Shinya Yamanaka Wins Prestigious Shaw Prize for Stem Cell Discoveries". 
  32. ^ "Gladstone's Shinya Yamanaka wins prestigious Shaw Prize". Bio-Medicine.org. June 11, 2008. 
  33. ^ "Professor Shinya Yamanaka Awarded the Shaw Prize". Kyoto University. June 17, 2008. 
  34. ^ "Professor Shinya Granted Sixth Sankyo Takamine Memorial Award". CiRA News Release. July 15, 2008. 
  35. ^ "Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science". 
  36. ^ Shinya Yamanaka, Recipient of the Canada Gairdner International Award, 2009. gairdner.org
  37. ^ BBVA Foundation Frontiers of Knowledge Award. Fbbva.es. Retrieved on 2012-10-08.
  38. ^ "Rinunce e Nomine - Nomina di Membri Ordinari della Pontificia Accademia delle Scienze" (Press release) (in Italian). Holy See Press Office. November 9, 2013. Retrieved November 12, 2013. 

External links[edit]

Awards
Preceded by
Michael Grätzel
Millennium Technology Prize winner
2012
Succeeded by
Stuart Parkin