S TE M CE L L S

Therapeutic Cloning Reaches Milestone

Last week stem cell researchers finally reached
a goal that has eluded them through more
than a decade of setbacks and scandal. Two
teams have independently derived human
embryonic stem cells by cloning adult skin
cells. The promise of the technique remains
tantalizing: replacement tissues for treat
ing diseases from diabetes to Parkinsons,
matched to the patient whose cells gave rise
to them. But the practical, ethical, and legal
hurdles are as high as ever. The method will
also have to prove its worth against a strong
competitor: a way to make personalized stem
cells that doesnt involve embryos.
The cloning technique, called
somatic cell nuclear transfer (SCNT;
see diagram), gained fame with the
cloning ofDolly the sheep 18 years ago.
Scientists soon learned to use SCNT
to clone cattle, mice, dogs, and other
animals. Researchers eagerly set out
to clone human cellsnot to replicate
humans, which most scientists strongly
oppose, but to generate early human
embryos from which stem cells could
be harvested. Although a decade ago
a South Korean scientist fraudulently
claimed success, human cells proved
resistant to cloning.
A year ago, Shoukhrat Mitalipov
and his colleagues at the Oregon
National Primate Research Center
in Beaverton finally used SCNT to
produce stem cell lines from the
DNA of human fetal and infant cells
(Science, 17 May 2013, p. 795). But
it wasnt clear whether the teams
tricks would work with cells from
human adults.
On 17 April, Dong Ryul Lee and
Young Gie Chung of CHA University
in Seoul and their colleagues settled
that question, reporting in Cell Stem
Cell the creation of embryonic stem
(ES) cell lines from skin cells of
two men, one 35 years old and one
75 years old. And on 28 April online
in Nature, Dieter Egli of the New
York Stem Cell Foundation (NYSCF)
Research Institute in New York City
and his colleagues describe going a
step further, making ES cells from a
32-year-old woman who has type 1
diabetes. They then prompted the ES
cells to become insulin-producing
cells, which are missing in people with
the disease.
Egli says that he and his colleagues have
put the insulin-producing cells into mice,
where they produced the hormone in response
to blood glucose levels. (That work is still
unpublished.) We are now one step closer to
being able to treat diabetic patients with their
own insulin-producing cells, he says.
Whether such personalized replacement
cells would help, especially in the long run,
remains uncertain, however. They would
likely fall prey to the same autoimmune attack
that killed a persons original insulin makers,
other scientists caution. Obtaining the human
oocytes needed to treat the millions with
DNA removed from
unfertilized oocyte
Long-awaited. Scientists have
used somatic cell nuclear transfer
to produce embryonic stem cells
from a type 1 diabetes patient.
They then differentiated the
stem cells into insulin-
producing cells.
Skin cells from
type 1 diabetes
patient
Differentiation into
insulin-producing
pancreatic cells
Embryonic stem cell lines
Proof of principle. Human embryonic stem cells
derived from a type 1 diabetes patient.
type 1 diabetes via SCNT would also pose a
major obstacle. Because extracting eggs from
women causes discomfort and poses health
risks, both groups paid the standard rate that
egg donors for in vitro fertilization procedures
receivein the United States, up to $10,000.
Given fair compensation, many women are
willing to donate oocytes, Egli maintains.
But spurred by ethical worries about undue
pressure on women, many organizations and
governments prohibit paying egg donors.
That includes the California Institute for
Regenerative Medicine, a major funder of
stem cell research, which put these cells off-
limits for its many grantees. Susan Solomon,
co-founder and CEO of the privately funded
NYSCF that funded Eglis work, predicts
that if the technique proves useful to create
effective therapies, friends or relatives
of someone sick will be willing to
donate oocytes.
Although early attempts at human
SCNT used hundreds of oocytes, Egli
says his teams method is now efficient
enough to derive a stem cell line from
a single egg donation cycle, which
usually produces between 15 and
20 oocytes. All three groups found that
efficiency seems to depend heavily on
the quality of the eggs used, with those
from younger donors superior to those
from older ones.
Legal issues still constrain SCNT.
Many governments forbid or otherwise
restrict its use with human cells. In
the United States, no federal funding
can be used for research that harms or
destroys a human embryo, so scientists
must set up separate lab space that
does not use any National Institutes of
Health or other federal grant money.
Several U.S. states have banned all
human SCNT research.
The political energy needed to
overturn those laws might be hard
to generate given that theres now an
embryo-free alternative to producing
patient-specific stem cells. By ramping
up the production of a handful of
genes, researchers can reprogram
mature cells into embryolike ones.
These induced pluripotent stem (iPS)
cells are already widely used to study
disease, and the first clinical trial with
them to treat macular degeneration
is under way in Japan. But some
scientists worry that iPS cells have
flaws of their own. Several studies
have found that the reprogramming
process is often incomplete, leaving
iPS cells with molecular traces of
462 2 MAY 2014 VOL 344 SCIENCE www.sciencemag.org
Published by AAAS
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NEWS&ANALYSIS
the mature cell they came from. (In mouse
experiments, SCNT-derived ES cells seem to
have fewer traces of their original cells than
iPS cells do.) Researchers are not yet sure
if the subtle differences are important to the
cellslater behavior.
Complicating the comparisons, sig
nificant differences exist among iPS cell
linesand perhaps among SCNT-produced
ES cells as well. An open question is, which
iPS cells should be the ones to compare to?
says Juan Carlos Izpisua Belmonte of the
Salk Institute for Biological Studies in San
Diego, California. Careful comparisons
could help scientists find more effective
ways to make patient-specific cells, whether
with oocytes or with other approaches, says
Ian Wilmut of the University of Edinburgh
in the United Kingdom.
The ability to compare the approaches in
human cells is key, says Doug Melton of the
Harvard Stem Cell Institute. The only way to
find out is to do these experiments.
-GRETCHEN VOGEL
E CONOMI C GE OL OGY
Seafloor Mining Plan Advances, Worrying Critics
If all goes as planned, the worlds
first commercial deep-sea mine
will open for business in 2016,
with engineers deploying a trio of
robots to claw high-grade copper
and gold ore from the sea floor
1500 meters down off Papua New
Guinea (PNG). Last week, after
years of dickering, PNGs govern
ment and Canada-based Nautilus
Minerals signed an agreement to
move forward with the ambitious
project. We were very happy to
get the deal done, says Nautilus
CEO Mike Johnston.
Critics arent so pleased.
Some marine biologists worry
the mining will start before
researchers can assess how it
will affect deep-sea ecosystems.
Others argue that national and
international regulators arent
ready to ensure that underwater
miners protect the environment.
The environmental impacts
are unknown [and] the mining
system is completely untested,
said Effrey Dademo of ACT
NOW!, a PNG group opposing the mine, in
a statement.
For decades, such debates were largely
academic, because mining at depths
greater than 1000 meters was considered
economically unworkable. But as
technology advanced, Nautilus and other
companies began prospecting. In some
locations, the sea floor is littered with
polymetallic noduleshard, round masses
of rock slowly precipitated from seawater
and bearing iron, manganese, nickel, and
other metalsthat miners could scoop up
with relative ease. In others, mineral-laden
water gushing from hydrothermal vents
has created rich outcrops. Although the
vents are harder to mine, the payoff can be
greater, because the deposits can include
both precious metals and rare earth elements
critical for computers, cellphones, and other
modern technologies.
For its project, Nautilus has targeted a
vent site known as Solwara 1, located near
seafloor cracks created as two tectonic plates
pull apart. Superhot fluids spew from deep
in the crust, mixing with the cold seawater
to form towers of ore-laden sediment known
as black smokers. Company surveyors
say the area, covering about 11 hectares, is
particularly rich in copper and gold.
It is also home to many kinds of sea
creatures, including tubeworms and bivalves,
according to environmental impact studies
sponsored by Nautilus. But the company
says it can mine without doing much long-
lasting damage, in part by taking steps to
control sediment plumes and relocate animal
communities. The overall effects [will be]
reversible and moderate, says
a 2008 company study, which
predicts that seafloor populations
would rebound within a few years
after mining ended.
Opponents are skeptical, with
some saying they doubt that the
PNG governmentwhich has
a 15% stake in the projecthas
the technical expertise to conduct
adequate and independent
oversight. Oceanographer
Cindy Van Dover of Duke
University in Durham,
North Carolina, who
helped Nautilus conduct
some of its preliminary
studies, concedes that
theres no way to know
what the impact will be.
Doing the studies that some
scientists would like to see
completed before mining begins
would be expensive, she notes,
with sustained seafloor research
costing $80,000 a day or more.
There are no concrete plans for
major new environmental impact
studies. I dont know how to get to that happy
place where the scientific community will let
the mining go on and be confident that we will
get the right amount of science, she says.
In the meantime, Nautilus says it plans
to move ahead with outfitting a vessel to
deploy its mining robots, including a 300-
ton behemoth that will chew through the sea
floor, and another that will pump a slurry of
mineral-rich ore to the surface. It hopes to be
operating within 30 months, Johnston says.
Nautilus may soon have company. Other
nations, including Fiji, are negotiating
seafloor mining rights. And the United
Nations little-known International Seabed
Authority, based in Kingston, has already
issued 19 permits for prospecting in
international waters.
-CAROLYN GRAMLING
www.sciencemag.org SCIENCE VOL 344 2 MAY 2014
Published by AAAS
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