8/2/2019 9AADFd01
1/2www.sciencemag.org SCIENCE VOL 335 2 MARCH 2012
NEWS&ANALY
CREDIT:VINCENTCENTERFORREPRODUCTIVEBIOLOGY,MASSACHUSETTSGENERALHOSPITAL
Since 2004, reproductive biologist Jonathan
Tilly of Massachusetts General Hospital in
Boston has fought a relatively lonely battle
to overturn one of the central dogmas of his
field. Men typically produce working sperm
as long as they live, but most textbooks sayfemale mammals are born with all the egg
cells, or oocytes, they will ever have. Tilly
has challenged that conventional wisdom,
arguing that in miceand perhaps also in
humansthere must be an ongoing source
of new eggs.
The proposal, its safe to say, hasnt been
warmly received by fellow reproductive
biologists. And Tilly didnt help his case in
2005 when he proposed that bone marrow
was a source of eggs in mice. (That idea
was discredited a year later.) But this week
online in Nature Medicine, Tilly and col-leagues report isolating rare cells in ovar-
ian tissue from adult women that can grow
in lab dishes and form immature oocytes.
This latest claim is earning some cau-
tious acceptance. As an egg biologist, Im
juiced about thi s, says David Albertin i
of the University of Kansas Medical Cen-
ter in Kansas City. The potential egg stem
cells could provide a lab-based model for
understanding how oocytes develop. And
they may help scientists devise new ways to
rescue the fertility of women who undergo
cancer treatments or who suffer from pre-
mature menopause.Tillys battle to win over colleagues is
far from over, however. There is no evi-
dence that these cells actually exist in vivo,
says Jock Findlay, a reproductive biolo-
gist at Prince Henrys Institute of Medical
Research in Clayton, Australia.
Since the 1950s, reproductive biologists
have thought that egg precursor cells stop
dividing about halfway through mamma-
lian fetal development, giving a newborn
female a finite number of potential eggs. A
baby girl, for example, is born with an esti-
mated 1 million oocytes. By puberty, that
number has declined to roughly 400,000.
During a womans fertile years, follicles,
the structures that host an oocyte and help
it to mature, are activated at a rate of about1000 per menstrual cycle. (Typically, only
one mature egg is released into the fallopian
tubes each cycle.) And once the oocyte sup-
ply runs low, menopause begins.
In 2004, Tilly and his colleagues pub-
lished data inNature that indicated that in
mice, too many oocytes die during each
menstrual cycle to sustain the supply of
eggs for the animals lifetime fertility. New
eggs, presumably from an unidentified stem
cell, must be coming from somewhere,
they proposed (Science, 12 March 2004,
p. 1593). Other researchers dismissed that
conclusion, saying the team had drastically
overestimated the rate of oocyte death.
Tilly persevered and in 2005, based o
bone mar rowtransplant experiments i
mice, he and colleagues proposed in Ce
that new oocytes might come from the mar
row and travel to the ovary via the bloodstream. A paper in Nature quickly dis
credited that idea (Science, 16 June 2006
p. 1583). In 2009, however, Tillys origina
idea got a boost when reproductive biolo
gist Ji Wu and his colleagues at Shangha
Jiao Tong University in China reporte
in Nature Cell Biology that they had iso
lated female germline stem cells from
adult mouse ovaries. To prove their case
the team genetically modified the putativ
stem cells so that they produced green flu
orescent protein (GFP) and then injecte
them into the ovaries of sterilized miceThose females gave birth to green-glowin
pups, demonstrating that the injected cell
had given rise to mature oocytes (Science
17 April 2009, p. 320).
It was still not clear, however, whethe
normal fertility and reproduction depen
on such cellsor whether they exist i
humans. And initial attempts by other lab
to find the mouse cells failed. Tilly says he
too, was frustrated at first. I put a person
on the protocol the day the paper was pub
lished. It took 10 months to get it to work.
still dont know why, he says.
In the new paper, Tilly and his colleaguereport that they have refined Wus cell
collection methods to isolate a more pure cel
population from mouse ovaries. And the
further describe fishing out similar cells from
human ovary tissue that Yasushi Takai, wh
works at the Saitama Medical Center in Japan
had previously collected from six women wh
had sex-reassignment surgery. The wome
were healthy and youngbetween 22 an
33 years oldand all agreed to have their fro
zen tissue used for the project.
Potential Egg Stem Cells Reignite Debate
REPRODUCTIVE B IOLOGY
Green egg. A human oocyte derived from oogonial
stem cells expressing green fluorescent protein.
mission between animals; it might also be
spread as an aerosol or by direct contact
between animals, he suggests.
Scientists are also puzzled by the viruss
ability to infect the fetus without killing
it. It is unusual that a pathogen that kills
mammalian cells in the petri dish can stay
in an organism as sensitive as a fetus for
such a long time without causing an abor-
tion, Beer says. He suggests that this trait
might be the viruss way of surviving the
winter, when no insects are around.
With biting midges expected to take
off again in May or sooner, animal health
experts are preparing for the next season of
Schmallenberg infection. Preliminary data
from two cows show that the animals that
had been infected earlier are immune to the
virus. But of course we dont know whether
this goes for all cows or how long this pro-
tection will last, Mettenleiter says.
Work is already under way on a vaccine.
At FLI, scientists are trying the classica
approach: inactivating the virus chemicall
and adding an adjuvant. Although the vac
cine might be easy to produce, the rigorou
testing demandsscientists have to be sur
it is safe in pregnant animalswill probabl
take a long time. Its very unlikely that thi
will be ready this year, Mettenleiter says
But it might be ready in 2013.
KAI KUPFERSCHMID
Kai Kupferschmidt is a science writer in Berlin.
Published by AAAS
8/2/2019 9AADFd01
2/22 MARCH 2012 VOL 335 SCIENCE www.sciencemag.org030
NEWS&ANALYSIS
A new paper by two developmental psychol-
ogists on the dearth of women in academic
science argues that the cause of the gender
imbalance is much easier to identify than
most researchers have posited. The solution
is also more obvious, they say, although that
doesnt mean it will be easy to implement
(see sidebar). Not surprisingly, their pro-
vocative assertions, in a paper titled When
Scientists Choose Motherhood, have stirred
the pot in an already contentious field.
Writing in the March/April issue of
American Scientist, Wendy Williams and
Stephen Ceci of Cornell University argue
that the traditional view of female under-
representation as a complex mixture of dis-
crimination, differential abilities, and career
preferences misses the mark. Instead, say the
husband-and-wife team, the evidence from
studies stretching back more than a decade
points overwhelmingly to the primacy of
the dynamics of family formation in West-
ern society, or, in a word, motherhood.
Williams and Ceci are certainly not the
first to note that the desire to have a fam-
ily hives off a significant fraction of women
who have made it through graduate school
and postdoctoral training in STEM (sci-ence, technology, engineering, and math-
ematics) fields and who stand at the brink
of an academic career. Despite their clear
interest and talent, the authors say, women
in their prime childbearing years are often
forced to make a stark choice between hav-
ing a family and pursuing a career for which
they have trained all their adult lives. Why
is it that women are given one 7-year inter-
val in which to amass a research portfolio
and have two kids? Williams asks, refer-
ring to the typical time frame for an assist
professor to earn tenure at a major resea
university. Thats crazy. Men dont have
do that. Its this societal-designed unfairn
thats rooted in biology.
Researchers from nearly every sci
tific discipline have spent decades exam
ing the reasons behind gender differen
in math and science, from the nursery
the Nobel Prize. Some studies have fou
systemic bias and discrimination, whet
deliberate or inadvertent, to be a major f
tor in the imbalance. Others argue that
slight edge for boys in mathematical a
ity among highly gif
students translates i
a significant differein adult success in ma
intensive STEM fields
third camp sees perso
pr ef erenceswork
with people versus thing
as some describe itas
driving force behind
divergent career choices
men and women.
In their new artic
which builds on a 20
paper in the Proceedi
of the National AcademSciences, the authors assert that a misdir
tion of resources toward problems that
longer exist has slowed progress. In parti
lar, they take issue with those who say t
correcting the gender imbalance will requ
a wholesale revamping of societal a
tudes toward women and a reworking of
nations educational system. What is m
important, they say, is to change the c
rent rigid system at universities of rewa
ing academic excellence. More flexibi
in the early years would allow them to h
a family and become full-fledged resear
ers, too, says Williams, who notes that hing three daughters influenced the coup
decision in 2005 to jump into this cont
tious field. But the current system doe
let them back in.
Its no surprise that an aggressive att
on those analyses would trigger strong reb
tals from researchers who are passion
about the topic. In particular, many resear
ers think Williams and Ceci have oversim
fied what they say is a very complex issue
selectively chosen data to bolster their cas
Is Motherhood the Biggest ReasonFor Academias Gender Imbalance?
S C I E N T I F I C C A R E E R SThe cells, which Tilly calls oogonial
stem cells (OSCs), are very rareonly
about 1 out of 10,000 ovarian cells. The
OSCs grow quickly in the lab, and they
spontaneously form cells that visually and
molecularly resemble immature oocytes.
To find out how the cells would behave in
an ovary, the scientists injected OSCs engi-
neered to make GFP into a piece of donated
human ovarian tissue and then implanted
the tissue under the skin of a mouse. When
they looked at the grafts 1 and 2 weeks
later, they found immature follicles with
green oocytes at their center.
Finding a human version of the cells
Wu isolated is very exciting, says Evelyn
Telfer, who studies oocyte development at
the University of Edinburgh in the United
Kingdom. But she and Albertini note that
the current experiments dont address what,
if any, role the apparent stem cells play in
normal ovaries. And Findlay says the cells
might be an artifact of the purification orculture methods the team used. Even the
green oocytes should be viewed with cau-
tion, as GFP-tagged cells can fuse with
unrelated cells, says Renee Reijo-Pera, a
reproductive biologist at Stanford Univer-
sity in Palo Alto, California.
The oocyte-like cells that grew from the
human OSCs were far too immature to try
fertilizing them, Tilly notes. And attempt-
ing such an experiment would need spe-
cial ethical oversight, he says. He and Telfer
have plans to see whether her techniques for
maturing oocytes in vitro work with OSC-derived cells. Whether the stem cells them-
selves could be a source of fertile oocytes
for in vitro fertilization attempts is doubtful,
Albertini says. He points out that expanding
cells in culture almost always leads to accu-
mulation of potentially harmful mutations.
Still, Albertini says, studying the cells
could help researchers. I think its a
great model. It could help us move toward
understanding how these incredible cells
[oocytes] are born and how they develop.
Tilly holds a patent on the OSCs, and he
has started a biotech company to explore
ways to use the cells to help improve fer-tility treatments. The company will screen
for compounds that encourage the cells
growth and development and will test
whether compounds in the cells might be
able to boost the fertility of aged eggs.
But even Tilly admits that the contro-
versy is unlikely to settle down anytime
soon: Whether the cells represent what
we believe they do? Thats going to take a
while to weed through.
GRETCHEN VOGEL
Family matters. Cornell psychologists Stephen Ceci and Wendy Williams
with two of their three daughters.
Published by AAAS
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