Due to the recent reversal of
stem cell research restrictions
in the United States, stem cells are back in the
news. According to
Essential Science Indicatorsfrom
Thomson
Reuters, the most-cited Hot Paper when searching on
"stem cell*" is "Induction of pluripotent stem cells
from adult human fibroblasts by defined factors"
(Takahashi K, et al., Cell 131[5]: 861-72, 30
November 2007), which accumulated 442 citations from
its publication up to February 28, 2009.
The chief researcher behind this paper is Dr. Shinya Yamanaka, who is
the Director of the Center for iPS Cell Research and Application (CiRA), at
the Institute for Integrated Cell-Material Sciences (iCeMS) at Kyoto
University in Japan. Dr. Yamanaka's citation record in the field of
Molecular Biology & Genetics includes 24 papers cited 2,274 times, and
he has several other Highly Cited Papers in other fields of the database as
well.
In this interview,
ScienceWatch.com talks with Dr. Yamanaka about the
2007 Cell paper as well as a 2008 Nature
Biotechnology paper and their impact on the stem cell
research field.
Would you tell us a bit about your educational
background and research experiences?
I received my M.D. at Kobe University in 1987. After working as a resident
in orthopedic surgery at National Osaka Hospital for two years, I decided
to enter the path to live as a scientist and got a Ph.D. in medicine at
Osaka City University in 1993. Soon I moved to the United States with my
family to work as a postdoctoral fellow at the Gladstone Institute of
Cardiovascular Disease, in San Francisco, CA. After returning to Japan in
1996, I worked as an assistant professor at Osaka City University School of
Medicine and got an associate professor position at the Nara Institute of
Science and Technology in 1999. In 2004, I landed a professorship at Kyoto
University.
Photo courtesy
of Dr. Shinya
Yamanaka, Kyoto
University.
When I was working as a postdoc at the Gladstone Institute of
Cardiovascular Disease, one of my purposes there was to master techniques
to generate knockout and transgenic mice. Embryonic stem cells became a
research material for me to make those mice. While making a transgenic
mouse that showed high expression of APOBEC1 protein in its liver, I found
that liver cancer occurred. Analysis of the cancer led me to the discovery
of a new gene, NAT1, which I found is essential to embyrogenesis and
differentiation potential of mouse embryonic stem cells. I became
fascinated by embryonic stem cell research thanks to this experience. When
I had my lab at the Nara Institute of Science and Technology, I decided to
make embryonic stem cells my lab’s main research theme.
Your team's November 2007 Cell paper,
"Induction of pluripotent stem cells from adult human fibroblasts by
defined factors," is the most-cited Hot Paper on the subject of stem
cells. Would you talk a little about this paper—its goals and
findings?
In August 2006, we reported in Cell that our lab generated ES-like
cells by introducing four genes—Oct 3/4, Sox2, Klf4, and
c-Myc—into mouse fibroblast cells (Takahashi K, Yamanaka S,
"Induction of pluripotent stem cells from mouse embryonic and adult
fibroblast cultures by defined factors," Cell 126[4]: 663-76, 25
August 2006). We named the cells "induced pluripotent stem cells" (iPS
cells). The next thing we were trying to achieve was, needless to say, the
reprogramming of human differentiated cells.
The 2007 Cell paper describes how we generated human iPS cells. We
added one procedure—lentiviral transduction of ecotropic receptor of
retrovirus before transduction of the same set of the four genes into adult
skin cells by retrovirus. The procedure improved the efficiency of
retroviral transduction and secured the safety of researchers actually
conducting the induction procedure. We successfully demonstrated that human
iPS cells were similar to ES cells in terms of many aspects, including
morphology, proliferation, gene expression, and teratoma formation. We also
showed that the iPS cells differentiated into functional cells such as
neurons and cardiac cells. Thus, the putative set of the four reprogramming
factors was shown to be effective in human cells.
Another of your papers, the 2008 Nature
Biotechnology paper, "Generation of induced pluripotent stem
cells without Myc from mouse and human fibroblasts," (Nakagawa M,
et al, 26[1]: 101-6, January 2008) is the most-cited Hot
Paper on stem cells in all of 2008. Why do you think this paper is
being cited so much so quickly?
We showed the effectiveness of the putative set of the four reprogramming
factors in mouse and human fibroblasts in our two papers—one
published in Cell in 2006 and the other in 2007. Considering
tumorigenicity attributed to the c-Myc insertion in the host genome, we
clearly demonstrated in the Nature Biotechnology paper that
Myc-devoid iPS cells can be generated by a modified protocol. Moreover, the
paper includes extensive comparison of reprogramming effects of Sox, Oct,
Klf, and Myc family genes. The data may be thought-provoking to many stem
cell biologists who have just started iPS research.
What are the hoped-for (or already realized)
applications for these pluripotent stem cells?
"Direct reprogramming technology
easily provides new pluripotent stem cells
without any ethical
controversy."
The applications for iPS cells that I believe will be realized in a few
years are disease model development, drug discovery, and toxicology. I also
expect to make the iPS cell technology available in regenerative medicine,
such as cell transplantation, when its safety is secured. I believe that
iPS cell technology should be applied to in-vitro use first. In
contrast, it will still require years of basic research before we can
overcome various obstacles, such as tumor formation, and realize
regenerative medicine. My main focus is to make my best efforts in order to
bring the iPS cell technology to patients at the earliest possible moment.
How much does the political climate affect your
research, if at all?
Since I announced in November 2007 that my lab generated human iPS cells,
the Japanese government and lawmakers have provided strong financial
support to advance iPS cell research, probably because the iPS cell
technology originated in Japan. I do not see that the political climate
affects iPS cell research in Japan, unlike in the US, where the change of
the administration from the Republican to the Democratic resulted in
reversing the nation’s policy on embryonic stem cell research.
Where do you hope to take this research in the
future?
Direct reprogramming technology easily provides new pluripotent stem cells
without any ethical controversy. There are still technical issues in iPS
cells, which I hope will be resolved soon. Although vigorous examinations
to confirm the safety of iPS cells, prior to clinical applications, are
absolutely necessary, I believe that iPS cells will provide great benefits
to patients through drug discovery and toxicology studies in the near
future, and then through cell transplantation therapy in the long-term
future.
Shinya Yamanaka, M.D., Ph.D.
Center for iPS Cell Research and Application (CiRA)
Institute for Integrated Cell-Material Sciences (iCeMS)
Department of Stem Cell Biology
Institute for Frontier Medical Sciences
Kyoto University
Kyoto, Japan
Mitsui K, et al., "The homeoprotein Nanog is
required for maintenance of pluripotency in mouse epiblast
and ES cells," Cell 113(5): 631-42, 30 May 2003.
Source:
Essential Science Indicators from
Thomson
Reuters.