Three Teams Reprogram Adult Cells for
Pluripotency
by Jeremy Cherfas
Biology Top Ten
Papers
Rank
Papers
Cites Jan-
Feb 08
Rank Nov-Dec 08
1
E. Bettelli, et al., "Reciprocal
developmental pathways for the generation of pathogenic
effector TH17 and regulatory T cells,"Nature, 441(7090): 235-8, 11 May 2006. [Harvard
Med. Sch., Boston, MA] *040YP
69
1
2
The ENCODE Project Consortium (E. Birney, et al.),
"Identification and analysis of functional elements
in 1% of the human genome by the ENCODE pilot
project,"Nature, 447(7146): 799-816, 14
June 2007. [80 institutions worldwide] *178FV
49
4
3
M. Veldhoen, et al., "TGFß in the
context of an inflammatory cytokine milieu supports de novo
differentiation of IL-17-producing T cells,"Immunity, 24(2): 179-89, February 2006. [MRC Natl.
Inst. Med. Res., London, U.K.; Howard Hughes Med. Inst., U.
Calif., San Francisco] *014KN
48
3
4
P.R. Mangan, et al., "Transforming growth
factor-ß induces development of the TH17
lineage,"Nature, 441(7090): 231-4, 11
May 2006. [U. Alabama, Birmingham; NIDCD, NIH, Bethesda,
MD] *040YP
47
5
5
K. Okita, T. Ichisaka, S. Yamanaka, "Generation of
germline-competent induced pluripotent stem
cells,"Nature, 448(7151): 313-7, 19 July
2007. [Kyoto U., Japan; Japan Sci. Tech. Agency, Kawaguchi]
*191GC
46
†
6
G.A. Tuskan, et al., "The genome of black
cottonwood Populus trichocarpa (Torr. &
Gray),"Science, 313(5793): 1596-1604, 15
September 2006. [39 institutions worldwide] *083YS
42
†
7
M. Wernig, et al., "In vitro
reprogramming of fibroblasts into a pluripotent
ES-cell-like state,"Nature, 448(7151):
318-24, 19 July 2007. [5 U.S. institutions] *191GC
40
†
8
N.J. Krogan, et al., "Global landscape of
protein complexes in the yeast Saccharomyces
cerevisiae,"Nature, 440(7084):
637-43, 30 March 2006. [10 institutions worldwide] *026OY
39
†
9
A.-C. Gavin, et al., "Proteome survey
reveals modularity of the yeast cell machinery,"Nature, 440(7084): 631-6, 30 March 2006. [Cellzome
AG, Heidelberg, Germany; EMBL, Heidelberg; MPI-MG, Berlin,
Germany; Austrian Acad. Sci., Vienna] *026OY
37
†
10
M. Komatsu, et al., "Loss of autophagy in
the central nervous system causes neurodegeneration in
mice,"Nature, 441(7095): 880-4, 15 June
2006. [Tokyo Metro. Inst. Med. Sci., Japan; Juntendo U.
Sch. Med., Tokyo; Osaka U. Grad. Sch. Med., Japan] *052SL
Sometimes one just has to wait. A media outpouring greeted the publication
in June 2007 of three papers that showed how adult skin cells can be turned
into pluripotent stem cells, capable of becoming any sort of cell. Now, a
year later, the judgement of the authors' peers agrees with that of the
press, and the results appear in the Top Ten list. Or rather, some of them
do.
The two papers published back to back in Nature, from Shinya
Yamanaka's group at Kyoto University and from Rudolf Jaenisch's group at
the Whitehead Institute, MIT, are there at #5 and #7. The third, published
in the inaugural issue of a new journal, Cell Stem Cell (N.
Maherali, et al., 1(1): 55-70, July 2007), is not, as its 28
citations during January-February 2008 were good enough to achieve Hot
Paper status but not quite sufficient for the current Top Ten. Kathrin
Plath at UCLA School of Medicine, one of two lead authors on that paper,
tells Science Watch® that "it's too bad for us,"
and speculates that one reason for the slight lag in citations might be
that Cell Stem Cell, being so new, was not included in PubMed's
database until February 2008, just after Science Watch's analysis
for this issue. That might have made it harder for some researchers to
cite.
Whatever the reason, all three groups discovered essentially the same
thing: that inserting a small group of four genes into an adult skin cell
"reprograms" that cell into something very like an
embryonic stem cell. Of course, none of the papers
actually goes as far as to call the reprogrammed cells "stem
cells"—the media, including Science Watch, did that. But
that is essentially what they are.
The stiffest test for pluripotency is that the cells should be capable of
forming the germline cells that give rise to future generations. All three
groups passed. By injecting the induced pluripotent stem (iPS) cells into
early-stage blastocysts, the researchers generated adult mice that included
cells derived from iPS cells in all their tissues, including germline
cells. Mating these chimeric mice with normal mice produced embryos in
which all cells were produced from iPS cells and, for Yamanaka's group,
live offspring.
The reprogramming to produce iPS cells really does seem to be complete. For
example, normal female cells inactivate one of the two X chromosomes.
Pluripotent cells from Plath and Konrad Hochedlinger's team reactivate the
silenced X chromosome and then randomly silence one of them when they
differentiate.
The reason for the interest in iPS cells is not hard to fathom. Stem cells
offer the potential for many different kinds of therapy, replacing damaged
or defective tissues. With research on embryonic stem cells severely
curtailed, especially in the United States, any improvement in the ability
to generate pluripotent cells from non-embryonic tissue is bound to attract
attention. Furthermore, the ability to make stem cells specific to an
individual patient makes these cells even more useful as replacements.
Until the publication of these three papers, the preferred approach was to
insert an adult nucleus into a fertilized egg. Somatic cell nuclear
transfer (SCNT) gave rise to Dolly the cloned sheep and brought down Woo
Suk Hwang in South Korea, after he fraudulently claimed to have created
human stem cells this way.
The SCNT approach is still being pursued, but induction of pluripotency now
seems to be in greater favor. Of course, problems remain. One of the genes
inserted into the skin cells to reprogram them was c-Myc, a known oncogene.
Yamanaka reported that around 20% of the offspring derived from iPS cells
developed tumors, which would not be acceptable in therapeutic use.
Yamanaka then reported a modified protocol for inducing pluripotency that
not only avoided the tumorigenicity associated with c-Myc but also resulted
in the generation of a higher percentage of iPS cells (see M. Nakagawa,
et al., Nature Biotech., 26(1): 101-6, January 2008; DOI:
10.1038/nbt 1374). At the same time Yamanaka and a group led by James
Thomson at the University of Wisconsin passed another milestone by using
the same sort of technique to induce human skin cells to become
pluripotent. Other types of adult cell followed in turn.
A separate hurdle is that these early studies use a retrovirus to insert
the reprogramming genes into the adult cells. This method inserts the genes
more or less at random into the DNA, which could result in the disruption
of essential functions. This, in addition to the use of c-Myc, could have
been responsible for some of the tumors seen. Many groups are working on
more benign viral vectors and some are even trying to avoid the need to
insert the actual genes, preferring to concentrate on the signals those
genes are producing.
The clinical importance of being able to create stem cells from a patient's
own cells cannot be overstated, one reason progress has been so rapid. The
big breakthroughs will undoubtedly figure here in Science Watch,
and eventually in practical medicine. One just has to wait.
Dr. Jeremy Cherfas is Science Writer at Bioversity International,
Rome, Italy.