G. HOFMANN
news and views
Figure 1 A little bird with a lot of variation.
Different stonechat populations live in
different climates and have different metabolic
rates. Wikelski et al.1 show that this variation
is inherent in the animal’s genes.
conditions. So the variations between birds
from the different populations could not
be due to physiological adaptations to their
respective local climates. Instead, the authors
suggest that the differences in metabolic rate
are specified by their genes.
What selective pressures shape the genetic
make-up of different stonechat populations?
Stonechats living in mild climates are yearround residents, whereas in locations with
harsh winter climates, the birds are long-distance migrants. So the higher metabolic rate
of stonechats from the Austrian and Kazakstan populations could be a consequence of
selective pressures associated with migration.
Wikelski et al. suggest that this is not the case
because, energetically, migration is a cheap
option compared with thermoregulation.
The high metabolic rates of the Austrian and
Kazakstan populations are more likely to be
selected for by occasional periods of freezing
temperatures during the breeding season.
Survival of warm-blooded animals in cold
climates is possible only if food consumption
is sufficient to meet the energy requirements
for maintaining body temperature. But high
metabolism has other costs besides increasing appetite — lifespan correlates inversely
with heart rate across a wide range of mammal species. Mammals with low metabolic
rates (and therefore slow heart rates) tend to
live longer. Indeed, the relationship between
metabolic rate and senescence is a central
issue in the study of longevity4. Higher metabolic rates lead to faster cell divisions and
a more rapid accumulation of mutations,
which might eventually impair cell function
and contribute to the ageing process. So the
lower metabolism of Kenyan stonechats will
allow them to survive better where food is
scarce, and might also permit slower senescence. This indeed appears to be a general
feature of tropical birds and mammals: the
pace of life is slow,but survival is high.
Wikelski and colleagues have looked at
how metabolic rate varied between populations, but other researchers have investigated
780
the variation within single populations. In
these studies, between half and two-thirds
of the inter-population variation was attributed to individual characteristics that
remained unchanged in individuals from
year to year5. So these studies also hint at a
genetic basis for metabolic rate. And seasonal6 or between-individual7 variations in
organ size and other aspects of body composition explained much of the individual
variation. It seems that the selective pressures that influence metabolism may be
complex, influencing metabolic rate through
affecting the density of mitochondria — the
energy-producing organelles inside cells —
or the size of the muscles or liver.
The genetic basis of metabolic rate has farreaching implications. For example, it is now
apparent that metabolism should be considered when selecting animal populations to
reintroduce into particular environments.
Recent reintroduction programmes brought
Scandinavian red kites to Scotland but
Iberian kites to England. Which is the better
source population? If Scandinavian kites
have a higher metabolic rate than their
Iberian relatives, they will be better adapted
to surviving cold conditions, but they will
need more food to sustain them.
The new study1 raises many other questions. Have island populations evolved lower
metabolic rates to cope with food scarcity?
Have equivalent selection pressures shaped
other features, such as insulating plumage or
pelt, to match the variations in metabolism?
Within a population, do individuals with
lower metabolic rates have a slower pace of
life? Wikelski et al. have demonstrated that
metabolic rate is a genetic characteristic that
can respond to selective pressure. But, as
these questions show, there is a lot more to
learn about how the environment shapes the
evolution of this characteristic.
■
Robert W. Furness is at the Institute of Biomedical
and Life Sciences, Graham Kerr Building,
University of Glasgow, Glasgow G12 8QQ, UK.
e-mail: [email protected]
1. Wikelski, M. et al. Proc. R. Soc. Lond. B
doi:10.1098/rspb.2003.2500 (2003).
2. Klaassen, M. Oecologia 104, 424–432 (1995).
3. Bryant, D. M. & Furness, R. W. Ibis 137, 219–226 (1995).
4. Kirkwood, T. B. L. Nature 270, 301–304 (1997).
5. Bech, C., Langseth, I. & Gabrielsen, G. W. Proc. R. Soc. Lond. B
266, 2161–2167 (1999).
6. Bech, C. et al. Comp. Biochem. Physiol. A 133, 765–770 (2002).
7. Bech, C. & Ostnes, J. E. J. Comp. Physiol. B 169, 263–270 (1999).
Cancer
A twist in a hedgehog’s tale
Matthew P. Scott
The genetics of development can often explain the genesis of cancer.
This now seems to be true for cancers of the gut, but the patterns of
gene expression in these tumours tell a tale with a twist.
rowth is beautifully orchestrated
during normal development to
produce animals of certain sizes.
Similarly, in adult tissues that constantly
regenerate, such as blood, gut and skin, a
delicate balance is established between cell
death and cell division. But genetic damage
can destroy the system of checks and
balances, sometimes causing cancer. Indeed,
it is becoming increasingly clear that many
tumours result from normal developmental
processes gone awry. Several types of cancer
have been linked to the disruption of the
‘hedgehog’ signalling pathway, which is
crucial to the normal development of many
tissues1,2. In this issue, Berman et al.3 and
Thayer et al.4 now implicate hedgehog signalling in the genesis of cancers of the digestive
system. Unusually, however, the fault does
not lie with the molecules that propagate
the hedgehog signal — instead, the tumours
make too much hedgehog.
The hedgehog protein (Hh) is so called
because it was discovered as the trigger for a
signalling pathway that organizes the pattern
of bristles on fruitfly larvae. But Hh is
involved in the development of many organs
and tissues in numerous animal species.
G
After being secreted from cells, Hh binds to
a receptor protein on the surface of cells
nearby.The receptor then transmits an intracellular signal, often culminating in changes
in gene expression. Most of the components
that transduce the signal within cells have
been conserved during more than half a
billion years of evolution and are recognizably similar in insects and mammals.
Two components of the Hh pathway are
Patched (Ptc), the cell-surface receptor protein to which the secreted signal can bind,
and Smoothened (Smo), an intracellular
protein that activates genes in response to the
Hh signal. In the absence of Hh, Ptc inhibits
the activity of Smo. But when a burst of
Hh molecules is secreted by nearby cells,
the molecules bind to Ptc, unleashing Smo,
which then transmits the signal through a
further chain of regulators. The result is the
activation of certain genes, some of which
encode proteins that trigger growth.
These regulatory relationships are the key
to understanding what happens in several
types of cancer. If Ptc is not sufficiently
active, Smo can be overactive and cells
can divide when they should not. The most
common cause of the deregulation is genetic
NATURE | VOL 425 | 23 OCTOBER 2003 | www.nature.com/nature
news and views
Earth science
The soaring, jagged peaks of the
world’s second highest mountain
range, the Andes, could owe their
stature not to the power of the Earth
but to that of the sea. So propose
Simon Lamb and Paul Davis in this
issue (Nature 425, 792–797; 2003).
Most mountain ranges are
created by the collision of two
continental plates, such as the
grinding action of India against Asia
that thrust up the Himalayas. But the
Andes are perched on a point where
an oceanic plate slips down beneath
a continental one. Great mountains
aren’t usually born of such meetings.
Heavy, dense oceanic plates tend to
slip underneath continental ones,
causing major earthquakes but not
world-class mountains. If the push
of the mid-Atlantic ridge on tectonic
plates were the only factor driving
up the Andes, one calculation shows
that they would be no more than
two kilometres high — half their
actual height.
Lamb and Davis argue that the
extra push comes from the fact that
the forces of the plate collision are
focused on a small area — a stretch
of the plate boundary where the
friction in the trench between the
Pacific and South America is
particularly high. The cold water
current that sweeps up the west
G. ROWELL/CORBIS
How do your mountains grow?
coast of Peru and Chile from high
southern latitudes encourages little
water evaporation, and therefore little
rain. That means there are no rivers
to dump worn mountain sediment
back into the ocean — sediment that
could act as lubrication. Instead, the
trench off the coast of the Andes is
rough and dry. That extra friction,
say the authors, helps to prop up
the mountains.
There could even be a positive
feedback loop in place, causing the
mountains to bulk up more and
mutation. Basal-cell carcinoma of the skin
— a common result of exposure to sunlight
— is most often triggered by ultraviolet damage to both copies of the ptc gene5,6. Mutation
of ptc has also been implicated in certain
brain7 and muscle tumours8. Cancer can also
result from mutations in smo that convert the
protein to a permanently activated form9.
Berman et al.3 and Thayer et al.4 now
implicate the Hh pathway in the genesis of
cancers of the digestive system. Rather little
has been understood about the origins and
growth of these often fatal forms of cancer,but
the role of Hh in the normal development of
these tissues hints that defective Hh signalling
might allow growth to explode. Curiously,
however, it seems that neither ptc nor smo is
mutated in tumours of the digestive tract.
Instead,the cancer cells make too much Hh.
Berman et al. surveyed the production
of Hh in cultured cells derived from several
different types of digestive-system tumour,
including those of the oesophagus, stomach,
biliary tract, pancreas and colon. They
detected Hh expression in all of these cell
more over time. The higher the
mountains grow, the drier the
coastline becomes — as any wet
air coming in from the Atlantic is
blocked by the towering peaks
— which in turn further reduces
erosion and props the mountains
up still more.
Complex relationships between
rock, air and sea have been found
before, although it’s usually
mountains that are thought to affect
climate, rather than the other way
around. The Himalayas, for example,
types, which led them to hypothesize that
this signalling molecule might be the trigger
for tumour growth. To test this idea they
tried to inhibit the growth of cultured
tumour cells by using a Hh-blocking antibody. Treatment with the antibody blocked
the growth of a wide range of tumour cells,
whereas the addition of Hh caused tumour
growth to spurt.
Meanwhile, Thayer et al. examined Hh
production in 20 human pancreatic cancer
biopsies and found that the protein was
aberrantly expressed in 70% of the specimens. To investigate whether Hh might contribute to the genesis of pancreatic cancer,
these authors examined transgenic mice in
which Hh had been overproduced in the
developing pancreas. All of these mice contained abnormal pancreatic cells that bore
similarities to precancerous cells observed in
a form of human pancreatic cancer.
Importantly, the link between the Hh
pathway and cancer of the digestive tract is
accompanied by ideas for treatment. Both
Berman et al. and Thayer et al. inhibited
NATURE | VOL 425 | 23 OCTOBER 2003 | www.nature.com/nature
are believed to have changed the air
flow enough to spark the formation
of the Indian monsoons. And as all
that rain weathered away the
mountains’ rocks, carbon dioxide
was taken out of the air and sent
down streams as carbonate, to be
buried at the bottom of the sea; this
extraction of greenhouse gas is
thought to have cooled the global
climate. But in the Andes, rather than
the mountains making the climate,
the climate might actually have made
Nicola Jones
the mountains.
tumour growth in mice with the drug
cyclopamine. This chemical is a teratogen —
a compound that can cross the placenta and
cause defects in a developing fetus.It was first
discovered in extracts from the corn lily, a
beautiful but treacherous flower often found
in alpine meadows. If a pregnant sheep eats
the plant, the fetus develops with cyclopic
facial features — the same defect that is
caused by inadequate Hh activity in people
and mice. It turns out that cyclopamine can
block the activity of Smo, so this, or other
drugs that affect the Hh pathway, have
potential as anti-cancer drugs10.
Both groups used a ‘subcutaneous
xenograft model’ of digestive-tract cancer
to test the effect of cyclopamine. In this
model, tumour cells are seeded under the
skin of immune-deficient mice. Berman
et al. waited until the tumours had grown
to a certain size, before injecting them with
cyclopamine each day.Remarkably,the treated
tumours regressed completely within 12
days. Meanwhile, Thayer et al. found that
treatment with cyclopamine reduced the
781