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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