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energy research initiative has a shot at
receiving backing by the Administration,
Joel Parriott, who helps the White House
Office of Management and Budget oversee
the budget for DOE’s Office of Science,
says that “it’s too early to tell.” He adds that
the Administration has already set its
energy policy priorities as increasing oil
drilling in Alaska’s Arctic National Wildlife
Refuge, clean coal, and hydrogen. However,
he says, “that doesn’t mean there isn’t room
for new things.”
With Congress close to passing an energy
bill that focuses on tax breaks for oil exploration and hybrid cars, it doesn’t look as if a
big push on solar energy will be one of those
“new things” anytime soon. But Dehmer
notes that progress on energy issues happens
slowly. “I’m trying to lay the groundwork for
a commitment on the scale of a major scientific user facility,” she says.
At least compared with DOE’s earlier
push for progress in hydrogen technology,
many researchers expect that a push on
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solar energy research will be a far easier
sell. “With hydrogen it was a lot more controversial,” Stupp says. “There are scientific
issues that are really serious [in getting
hydrogen technology to work]. With solar,
it’s an idea that makes sense in a practical
way and is a great source of discovery.” If
that research and discovery doesn’t happen,
Lewis says he’s worried about what the
alternative will bring: “Is this something at
which we can afford to fail?”
–ROBERT F. SERVICE
Re p r o d u c t i v e B i o l o g y
A Powerful First KiSS-1
CREDIT: GETTY IMAGES
Puberty researchers are finding that the protein kisspeptin and its receptor are central
to this sexual maturation
Both anticipated and dreaded,
puberty is rarely fun. From
swelling breasts and sprouting
hair to cracking voices and unexpected urges, this transition is
almost always awkward, especially if puberty comes earlier or
later than normal. It is a rare
teenager who has not wondered,
“Why is this happening to me?”
The body’s awakening into
sexual maturity is no less puzzling
for developmental biologists and
endocrinologists. And they have
an equally straightforward question: How does the body know
when, exactly, to unleash the cascade of hormones that change
face, voice, height, bone structure,
and sexual organs into those of a
fertile adult? The emerging
answer, it seems, could have come
from a teenage romance novel:
Puberty starts with a kind of kiss. Are you ready? A protein called kisspeptin helps trigger the
Recent studies have shown flood of hormones that marks puberty.
that a protein called kisspeptin is
Scientists hope the two proteins might
a key trigger of the complex chain of physiological reactions that readies the body for help them solve long-standing puzzles
sexual maturity. Without this signal, people, about the start of puberty, such as how the
as well as mice and other mammals, stay in a body revives the hormone production that
preteen limbo and never fully grow up. Dis- is prevalent in fetal and newborn developcovering the involvement of kisspeptin and ment but then mysteriously disappears durits receptor, a protein called GPR54, in ing childhood, and how puberty might be
puberty “is a major breakthrough in repro- influenced by nutrition and other metabolic
ductive physiology,” says Manuel Tena- factors. Preliminary evidence suggests,
Sempere of the University of Cordoba in moreover, that the protein pair may even
Spain. Indeed, the duo was one of the most- play a lifelong role in regulating sex
discussed topics at a recent meeting on the hormones and reproduction.
The topic is more than academic. For
control and onset of puberty.*
some children, puberty doesn’t happen at
* 6th Puberty Conference, Evian, France, 26–28 May.
the right time: Girls who start to develop
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VOL 309
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breasts and pubic hair as young as 6 years
old, and boys at 17 who still sing soprano
often end up at the pediatrician’s off ice
looking for answers. Although the physical
consequences of being an early or late
bloomer remain unclear, the social consequences can be signif icant. Boys who
develop late may face brutal taunting
because of their small stature and underdeveloped muscles. And early-developing
girls “have higher rates of depression, substance abuse, and teenage pregnancies,”
Pierre-André Michaud, a specialist in adolescent medicine at the University of Lausanne in Switzerland, said at the meeting.
Consequently, physicians are eager to
understand how puberty is controlled and
whether they can, or should, safely delay or
accelerate it in certain cases.
KiSS-1-ng partner
It was GPR54, not kisspeptin, that
appeared first as a player in puberty. The
initial clue was a 20-year-old man in Paris
who had undeveloped testes, sparse pubic
hair, and the bone maturity of a 15-yearold; such lack of sexual development
is called idiopathic hypogonadotropic
hypogonadism (IHH). Doctors soon discovered that the man was not the only one
in his family to fail to complete puberty:
Three of his four brothers were similarly
affected, and one of his two sisters had
experienced only a single menstrual period
in her life—at age 16. All had abnormally
low levels of sex hormones.
It turned out that the parents of this family were first cousins and, as a team led by
Nicolas de Roux of INSERM in Paris
reported in 2003, both mother and father
carried a mutation in one copy of their
GPR54 gene. The affected children had all
inherited two mutated copies of the gene.
Other researchers had shown that GPR54
acts as a receptor for kisspeptin, so de Roux
and his colleagues suggested that the molecular embrace between the two proteins
might be a player in the first steps of puberty.
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A month after de Roux’s paper was hormonal signal. In cell-based assays, who become too thin, for example,
published, that suggestion got a major kisspeptin “is one of the most powerful acti- become infertile and stop having periods.
boost. Stephanie Seminara, Yousef vators of GnRH neurons ever seen,” says And people and mice with mutations in
Bo-Abbas, and William Crowley of Har- Robert Steiner of the University of Wash- the genes coding for leptin or its receptor
vard Medical School in Boston and their ington, Seattle. And in February, endocri- are infertile, apparently because of a
colleagues reported that six members of a nologist Tony Plant of the University of failure to go through puberty. But further
large Saudi Arabian family, all diagnosed Pittsburgh in Pennsylvania reported in the research failed to turn up direct conwith IHH, also had mutations in
nections between leptin and
their GPR54 genes. They also
GnRH neurons.
found that an unrelated patient
There’s early evidence that
with IHH carried mutations in
kisspeptin may help mediate
both his copies of the gene. In
such a connection. In the June
the same paper, researchers
issue of Endocrinology, Tenafrom Paradigm Therapeutics in
Sempere reports that rats kept
Cambridge, U.K., reported that
on a restrictive diet produce
mice lacking the GPR54 gene
less messenger RNA (mRNA)
also failed to go through the
from KiSS-1, consistent with
rodent version of puberty.
the idea that the gene responds
Scientists at the time knew
to leptin and other hormones
very little about GPR54. They
that signal the body’s nutriknew its gene was expressed in
tional status. They also found
the brain and the placenta, and
that administering kisspeptin
they knew the protein was a
to underfed juvenile rats
receptor for kisspeptin, which is
could jump-start their delayed
encoded by a gene called KiSS-1.
puberty, perhaps bypassing the
KiSS-1, on the other hand, was
need for leptin to reach some
fairly well known, but not among
puberty threshold.
endocrinologists. The gene was
The KiSS-1 neurons, Steiner
discovered by cancer researchers
says, may integrate signals from
at Pennsylvania State College of Leading lights. The neurons that express the KiSS-1 gene (white dots) a wide variety of body systems,
Medicine in Hershey, Pennsylva- cluster in a region of the hypothalamus known to respond to sex hormones. such as how much food is availnia, who noticed that it played a
able and even circadian clues
role in the ability of tumor cells to move and Proceedings of the National Academy of such as time of day and season of year. The
metastasize. (The romantic connection to Sciences that within 30 minutes of injecting connection may sound surprising, but
puberty is accidental: The researchers juvenile male rhesus monkeys with researchers have long known that GnRH
named the gene for the famous Hershey kisspeptin, the animals’ levels of LH and other sex hormones follow a daily
chocolate drops.)
increased 25-fold.
rhythm and that the first hormone surges of
Because of KiSS-1’s known role in cell
puberty tend to occur at night. Steiner says
motility, scientists initially thought that the Puberty’s puzzles
he and his colleagues are looking for conkisspeptin-GPR54 pairing might influence Those results solidify the fundamental role nections between KiSS-1 neurons and the
puberty by directing so-called GnRH of kisspeptin and GPR54 in puberty’s onset, brain’s circadian clock to see if they might
neurons to the correct part of the brain. but it is not the whole story. “I’m not sure link the circadian and reproductive systems.
GnRH neurons were identif ied more this is the discovery of the Holy Grail for But such work is still speculative. “The
than 3 decades ago as the source of puberty,” Steiner says. “You need to have KiSS-1 neuron is far from characterized,”
gonadotropin-releasing hormone (GnRH), this circuit operating for sure, but the con- de Roux cautions.
a brain chemical that prompts the pituitary clusion that this is the ultimate switch for
There is also evidence that the
gland to produce follicle stimulating hor- puberty is probably premature.”
kisspeptin-GPR54 signal helps regulate
mone and luteinizing hor mone (LH).
A missing link, for example, is what reproduction long past the first stirrings of
Those signals in turn stimulate production turns the circuit on. Steiner and neuro- puberty. Steiner and his colleagues
of sex hormones such as estrogen and endocrinologist Allan Herbison of the Uni- reported online in the 26 May issue of
testosterone in the ovaries and testes.
versity of Otago in Dunedin, New Zealand, Endocrinology that KiSS-1 neurons in the
Kallmann syndrome, another condition are studying the neurons that produce the mouse brain carry estrogen receptors and
in which patients fail to go through puberty, protein to find out what signals influence that levels of KiSS-1 mRNA in the brains of
is caused by the improper migration of them. One of the most intriguing ideas is adult mice are modulated by injections of
GnRH neurons during fetal development, that kisspeptin might be connected to the the hormone. And a group led by Keiichiro
so researchers wondered whether a similar hormone leptin: Steiner said at the meeting Maeda of Nagoya University in Japan
problem affected IHH patients with GPR54 that he has preliminary evidence that at reported online 23 June in Endocrinology
mutations. But subsequent studies have least half of the neurons that express KiSS-1 that when they used antibodies to block the
since shown that GnRH neurons are present also carry receptors for leptin.
kisspeptin-GPR54 signal in adult female
in the correct place and quantity in the
A few years ago, many scientists rats, the LH surge that triggers ovulation
GPR54-knockout mice.
thought that leptin, which is produced by didn’t occur. “It is not just a switch that is
Instead, the mutations may prevent the fat cells, was the key puberty trigger, pro- activated once,” Tena-Sempere says. It
release of GnRH; GnRH neurons express viding a way for the body to delay sexual seems that, like the best kisses, KiSS-1 has
GPR54 receptors, and their activation by maturation until it has enough stored long-lasting consequences.
kisspeptin prompts the cells to release their energy to support reproduction. Women
–GRETCHEN VOGEL
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VOL 309
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CREDIT: R. STEINER/UNIVERSITY OF WASHINGTON
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