Hans R. Schöler talks
with ScienceWatch.com and answers a few questions
about this month's New Hot Paper in the field of Clinical
Medicine. The author has also sent along an image of
Photo: MPI Muenster/Sarah Eick
Article Title: Pluripotent stem cells induced from
adult neural stem cells by reprogramming with two
Authors: Kim, JB;Zaehres, H;Wu, GM;Gentile, L;Ko,
K;Sebastiano, V;Arauzo-Bravo, MJ;Ruau, D;Han, DW;Zenke,
Journal: NATURE, Volume: 454, Issue: 7204, Page: 646-U54,
Year: JUL 31 2008
* Max Planck Inst Mol Biomed, Dept Cell & Dev Biol,
Rontgenstr 20, D-48149 Munster, Germany.
* Max Planck Inst Mol Biomed, Dept Cell & Dev Biol,
D-48149 Munster, Germany.
* Univ Aachen, Sch Med, Rhein Westfal TH Aachen, Inst
Biomed Engn,Dept Cell Biol, D-52074 Aachen, Germany.
Why do you think your paper is highly
Tremendous debate has arisen in both the scientific community and the
general public over the past decade regarding the derivation and use of
stem cells. Though the derivation of human embryonic
stem cells is fraught with ethical considerations, the potential
application of these cells in areas such as regenerative medicine, for
example, may lead to curative therapies and thus holds immense clinical
The discovery of induced pluripotent stem ("iPS") cells, first in mice and
then in humans, has opened up new avenues for generating pluripotent cells
from the somatic cells of individual patients, thereby obviating ethical
Originally, iPS cells were generated via the retroviral gene transfer of
the four transcription factors: Oct4, Sox2, Klf4, and c-Myc. However, as
Klf4 and c-Myc are well-known oncogenes, the iPS cells generated by and
expressing these factors were not of clinical use.
Our paper was the first demonstration of reducing this cocktail to the two
factors Oct4 and Klf4, making iPS generation not only easier in the lab,
but also potentially safer in the clinic.
The iPS cells generated were similar to embryonic stem cells, as judged by
molecular and developmental properties, including their ability to
contribute to development of the germline and to form chimeras. The success
of this work lies in the ability to complement already existing factors.
The somatic cells used in our study express higher endogenous levels of two
of the above transcription factors—Sox2 and c-Myc—and thus the
addition of Oct4 and Klf4 completed the necessary quartet.
Colony of iPS
cells that originate from reprogramming of neural
stem cells with two factors.
"MPI Muenster/Jeong Beom Kim"
With this paper, we are the first lab to prove the hypothesis that the
number of exogenously added reprogramming factors can be reduced when using
somatic cells that express appropriate endogenous levels of the
complementing, or remaining, reprogramming factors. Further work may see
the use of small-molecule compounds in lieu of gene transfer to induce the
endogenous expression of these factors.
Finally, since we used adult neural stem cells as the starting somatic cell
population, we are also the first lab to generate iPS cells from adult stem
cells, thereby combining adult, embryonic, and iPS cell research in one
Does it describe a new discovery, methodology, or
synthesis of knowledge?
The genetic complementation of endogenous factors with exogenous factors to
generate iPS cells can be considered a new discovery in the field of
cellular reprogramming. By reducing the number of exogenous factors needed
to successfully generate iPS cells, we have simplified the gene transfer
methodology, while, at the same time, rendering the generated iPS cells
Would you summarize the significance of your paper
in layman's terms?
The generation of pluripotent stem cells ("allrounder") from somatic cells
from each individual patient is feasible with the addition of just two
factors. Subsequent work, which we have published in Cell and
Nature this year, narrows down the factors even further.
In the latter we show direct reprogramming of human neural stem cells by
Oct4. Thus we know now that the transcription factor Oct4 alone can do the
job in both mice and humans. Just think about it for a moment: just one
factor can turn a somatic stem cell into cell that can give rise to every
cell within our body. Oct4 is the earliest expressed gene known to encode a
transcription factor which is developmentally regulated during mammalian
How did you become involved in this research, and
were there any problems along the way?
Our lab has had a long-standing interest in reprogramming research. We have
looked at methods to induce pluripotency in the mouse system using somatic
cell nuclear transfer and cell fusion. A key ingredient in this work has
been the development of a reliable reprogramming marker system consisting
of an Oct4 promoter–GFP transgene.
But it all started 20 years ago, when I described and cloned the
transcription factor Oct-4, which we associated with cellular pluripotency.
The scientific community at that time speculated that a cocktail of
"reprogramming" factors might be applied to somatic cells in an effort to
induce pluripotency. Shinya Yamanaka was the first scientist to
conclusively bring this idea to fruition in the mouse system (Takahashi K,
Yamanaka S, "Induction of pluripotent stem cells from mouse embryonic and
adult fibroblast cultures by defined factors," Cell 126:
663-76, Aug 25, 2006).
Since that discovery, we have accomplished three major feats that have
allowed us to undertake our study. We have developed the technologies to
cultivate neural stem cells and to transfer the transcription factors into
somatic cells as well as the methodology to compare the generated iPS cells
at the molecular and developmental levels to embryonic stem cells.
Where do you see your research leading in the
The direct reprogramming of almost any type of somatic cell using gene
transfer is now readily feasible in the lab. The replacement of gene
transfer technology with recombinant proteins and/or small molecules is now
possible, but with very low efficiency. The routine use of these new
technologies to develop iPS cells would be a huge step forward.
For example, patient-specific iPS cells and cells derived from them would
be of great value in drug discovery and toxicology studies. The ultimate
goal is to enable the safe and effective use of iPS-derived cells in cell
transplantation therapy. However, many hurdles must be overcome before the
clinical utility of iPS cells comes to pass.
Do you foresee any social or political implications
for your research?
Intense debate on human embryonic stem cell research continues in my home
country of Germany and in the USA, where I had my lab for five years.
Personally, I feel a sense of relief since these alternate
cells—induced pluripotent stem cells—have been developed and
are now on the market.
Although human embryonic stem cells are still the gold standard of
pluripotent cells, clinical applications with pluripotent stem cells may be
more easily achieved with iPS cells. Well, we will see.
Professor Dr. Hans Schöler
Department Cell and Developmental Biology Director
Max Planck Institute for Molecular Biomedicine
Münster, Germany Web
KEYWORDS: HUMAN SOMATIC-CELLS; HUMAN FIBROBLASTS; DEFINED
FACTORS; EXPRESSION; MOUSE; GENERATION; ONCOGENE; GENES; SOX2;