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DNA damage
O2 stress
Wild type
Apoptosis/normal ageing
Apoptosis
p66-/-
No apoptosis/slow ageing
Apoptosis
p53-/-
No apoptosis/? rate of ageing
No apoptosis/cancer
Figure 2 Cellular response to oxidative stress and DNA damage. In wild-type mouse cells, both agents
induce apoptosis. In mutants that lack both copies of the p66shc gene, oxidative damage does not
induce cell death but DNA damage does. In mutants lacking both copies of the p53 gene, neither
agent induces cell death.
ed by DNA damage (Fig. 1c) and, like p66shc,
can lead to either repair (by arresting the cell
cycle) or apoptosis. Migliaccio et al. show
that cells from mice deficient in p53 are also
resistant to killing by reactive oxygen species.
So why don’t p53-deficient mice also live
longer? The problem is that these cells are
also defective in the response to other forms
of DNA damage, leading to a high frequency
of cancer (Fig. 2) that would override the
benefits of any possible extension to lifespan.
That said, it would be interesting to use other
assays, such as microarray analysis of gene
expression, to work out whether any aspects
of ageing are slowed in p53 mutant cells.
Interestingly, however, knocking out p53
can extend lifepsan in a specific setting, when
the mTR (telomerase RNA) gene is also disrupted. Mice that lack mTR alone experience
telomere shortening with each generation
(telomeres are specialized structures on the
end of chromosomes). After six to seven generations of breeding, this leads to sterility
and other defects9.When both p53 and mTR
are disrupted, mice can survive an extra one
or two generations, presumably because the
defect in p53 prevents activation of the apoptotic pathway that would normally be turned
on by the short telomeres10.
Important questions remain. First, can
the longer lifespan of the p66shc-defective
mice be generalized to strains other than the
129 strain examined by Migliaccio and colleagues? If so, this would rule out the possibility that the 129 mice are limited by a specific defect in the repair of oxidative damage.
Second, why do mammals have a p66shc at all,
if mice that lack it live longer with few side
effects? Migliaccio et al. note that the p66shcdeficient mice do, in fact, have abnormallooking lung tissue, but the authors do not
know the pathological significance (if any) of
this. It will also be important to test whether
the p66shc-deficient mice have reduced fertility. Third, how important is oxidative damage and the response to it in human ageing?
The human lifespan is very long so, theoretically, any problem limiting the mouse lifespan could have been corrected in humans.
One hint that ageing mechanisms in humans
and mice overlap would be a demonstration
NATURE | VOL 402 | 18 NOVEMBER 1999 | www.nature.com
that calorie restriction helps people to live
longer. Preliminary findings indicate that
the physiological changes associated with
calorie restriction in rodents also occur in
primates11.
We may be at a watershed in the study of
ageing. A more robust response to oxidative
damage is associated with longer life in
mutants of the nematode worm12,13, yeast14
and the fruit fly15,16. Migliaccio and col-
leagues are the first to show that a simple
genetic modification of this response can
increase lifespan in a mammal. In humans,
drugs given later in life might circumvent any
costs in development or reproduction. We
should therefore look forward to a growing
research area nurtured by, if not the fountain
of youth, more than a trickle of hope.
■
Leonard Guarente is in the Department of Biology,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, USA.
e-mail: [email protected]
1. Migliaccio, E. et al. Nature 402, 309–313 (1999).
2. Harmon, D. J. Gerontol. 2, 298–300 (1956).
3. Medawar, P. B. Modern Quarterly 1, 30–56 (1952).
4. Williams, G. C. Evolution 11, 398–411 (1957).
5. Weindruch, R. et al. J. Nutr. 116, 641–654 (1986).
6. Brown-Borg, H. M. et al. Nature 384, 33 (1996).
7. Rozakis-Adcock, M. et al. Nature 360, 689–692 (1992).
8. Levine, A. J. Cell 88, 323–331 (1997).
9. Blasco, M. A. et al. Cell 91, 25–34 (1997).
10. Chin, L. et al. Cell 97, 527–538 (1999).
11. Roth, G. S. et al. J. Am. Geriatr. Soc. 47, 896–903 (1999).
12. Martin, G. M. et al. Nature Genet. 13, 25–34 (1996).
13. Ewbank, J. J. et al. Science 275, 980–983 (1997).
14. Kennedy, B. K. et al. Cell 80, 485–496 (1995).
15. Orr, W. C. & Sohal, G. S. Science 263, 1128–1130 (1994).
16. Parkes, T. L. et al. Nature Genet. 19, 171–174 (1998).
Geochemistry
Molten rocks in motion
Michael R. Perfit
e only see the Earth’s mantle in action
when it melts and rises to the surface,
most spectacularly during a volcanic
eruption. The 70,000-km-long, global network of mid-ocean ridges is the site of the
most abundant and steady supply of magma
(and after cooling, new crust) on Earth.
Detailed investigations during the past two
decades have greatly expanded our view of
volcanic and tectonic processes at ocean
ridges, but we still have a limited understanding of how magma is delivered to, and
concentrated in, the relatively narrow zones
of volcanic and hydrothermal activity along
spreading ridges.
On page 282 of this issue, Spiegelman and
Reynolds1 attempt for the first time to distinguish between different dynamic models of
mantle melting beneath ocean ridges by
comparing them with geochemical data2,3
from basalts (volcanic rock) that erupted in
the northern section of the fast-spreading
East Pacific Rise. There is not yet a consensus
on the style of mantle melting, but Spiegelman and Reynolds have taken a first step
towards trying to reconcile theory with
observation.
Chemically, samples of mid-ocean ridge
basalts from the oceanic crust have provided
indirect information about the composition
of the mantle and the chemical and physical
processes that can modify magma, but have
W
© 1999 Macmillan Magazines Ltd
so far given little insight into the dynamics of
melting or upwelling of mantle material4,5.
How and where the mantle melts, how
magma interacts with the solid mantle
matrix on its way to the sea floor, how the
chemistry of basaltic magma varies in space
and time and how the upper oceanic crust is
formed, are all questions that have yet to be
answered.
Two fundamentally different theories
have been proposed to explain the volcanic
activity associated with spreading ridges6,7.
One model assumes that magma flow is
dynamic or ‘active’ (it buoyantly rises and
helps drive plates apart) and the other
assumes that magma rises passively (it rises
in response to the plates being pulled apart).
In the first case, magma is concentrated in a
narrow zone directly below the ridge axis,
whereas in the other magma converges
from a wide area below the ridge towards this
narrow zone (Fig. 1, overleaf). In both models magma is concentrated beneath the ridge
crest, but tests to determine which model is
correct have been wanting.
Geophysical studies8 and results from the
recent MELT experiment9 — the most comprehensive seismic and electromagnetic
study across the southern East Pacific Rise —
have shed new light on our view of the upper
mantle where basalts form. Both methods
used can detect the presence of magma
245
because seismic velocities change when they
pass through molten rocks and electrical
conductivity is much higher in magma
than in solid rocks. In the MELT area,
seismic data9 indicate that small amounts
of magma (* 2%) are asymmetrically distributed around the ridge axis, in a region
extending much farther to the west (up to
350 km) than to the east, and to depths possibly as great as 130 km. The electromagnetic
evidence10 is consistent with this finding but
also suggests that magma may be present to
even greater depths and that the amount of
magma is much lower in the east than the
west. These results support models for passive magma flow, because the magma
appears to converge on the ridge axis from
such a wide area in the mantle. But is this
consistent with what volcanic and geochemical studies have found along other segments
of the East Pacific Rise?
Recent seafloor studies and radioactive
dating of basalts on the East Pacific Rise indicate that volcanic eruptions occur both ‘onaxis’ — that is, within a narrow zone along
the ridge summit — as well as ‘off-axis’ in the
crestal plateau, in a region up to ` 5 km
away11–13 (Fig. 2). Some of the basalts found
off-axis are geochemically distinct from
‘normal’ basalts recovered closer to the ridge
axis. In an upcoming paper, Reynolds and
Langmuir3 show that off-axis basalts in the
12° N region of the East Pacific Rise are more
depleted in certain elements such as Na, P,
Ti and Zr, compared with basalts recovered
Asthenosphere
Off-axis
flows
from the ridge axis. Given what we know (or
think we know) about melting and magma
flow below ridges, it is difficult to explain
such a spatial variation in composition.
We may now have an answer. The melt
models discussed by Spiegelman and
Reynolds1 show that off- and on-axis magmas will differ in composition depending on
whether the flow is passive or active in the
mantle. The geochemical characteristics of
basalts from 12° N are consistent with passive
flow, whereby small amounts of magma
formed over a wide region in the mantle converge on the volcanic zone. These findings
are significant because they are consistent
with results from the MELT experiment.
They suggest that basalt chemistry can be
used as an independent tool to study
processes associated with ridge dynamics
that are difficult to test with geophysical
techniques and geodynamic models alone.
But some problems remain. First, it is not
easy to say with certainty which basalts
actually erupted off-axis, and which erupted
at the ridge axis and were subsequently transported to an off-axis location by spreading.
Second, the 12° N area is one of the few areas
of the East Pacific Rise where enriched basalts
are located on-axis and depleted types are
found off-axis. The opposite is true in other
parts of the northern East Pacific Rise12,13.
How do these areas fit into the picture? Can
different segments only a few hundred kilometres apart have different mantle melting
styles? Is the distribution of basalt types per-
Ridge axis
Magma
chamber
Oceanic
crust
Lithosphere
Figure 1 Cross-section through a mid-ocean ridge. Chemical differences between volcanic rocks
found at the ridge axis and at off-axis locations support a passive model of mantle flow, as discussed
by Spiegelman and Reynolds1. In passive flow, upwelling of ‘liquid’ magma (solid lines) and solid
mantle (dotted lines) is in response to (rather than the cause of) plate motion. The magma is
concentrated at the ridge crest but converges from a wide area beneath the ridge.
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© 1999 Macmillan Magazines Ltd
M. PERFIT & D. FORNARI
news and views
Figure 2 Examples of off-axis pillow lavas that
erupted along fissures a few kilometres from the
axis of the East Pacific Rise at 9° 328 N.
haps related to ocean spreading cycles (for
example, active ridges versus those that are
starved of magma)? Finally, geophysical data
such as those obtained during the MELT
experiment do not exist for the northern East
Pacific Rise, so it is unclear if those results
apply here.
Spiegelman and Reynolds’ attempt to pin
down a conceptual model for mantle melting is but a first step towards a more complete understanding of melting processes in
the upper mantle and their role in creating
ocean crust. Despite some widely spaced
sampling of basalts along the East Pacific
Rise, few areas of the global mid-ocean ridge
system have been sampled in detail. So how
applicable this model is to other ocean
ridges, or even to other fast-spreading segments of the East Pacific Rise, remains to be
tested. Correlating the composition of surface basalts and their distribution on the sea
floor with models of magma generation in
the mantle is a challenge that must be met by
marine geologists, geophysicists and geochemists in the coming decades. Fine-scale
mapping and sampling of more tectonically
diverse segments of the global ridge system
will allow us to form a better picture of the
mantle processes that ultimately determine
the volcanic and tectonic activity that creates
the oceanic crust.
■
Michael R. Perfit is in the Department of Geological
Sciences, University of Florida, 241 Williamson
Hall, PO Box 112120, Gainesville,
Florida 32611–2120, USA.
e-mail: [email protected]
1. Spiegelman, M. & Reynolds, J. Nature 402, 282–285 (1999).
2. Reynolds, J. et al. Nature 359, 493–499 (1992).
NATURE | VOL 402 | 18 NOVEMBER1999 | www.nature.com
news and views
3. Reynolds, J. & Langmuir, C. Earth Planet Sci. Lett. (in the press).
4. Langmuir, C. et al. in Mantle Flow and Melt Generation at MidOcean Ridges (eds Phipps Morgan, J., Blackman, D. & Sinton, J.)
183–280 (American Geophys. Union, Washington DC, 1992).
5. Niu, Y. J. Petrology 38, 1047–1074 (1997).
6. Spiegelman, M. & McKenzie, D. Earth Planet. Sci. Lett. 83,
137–152 (1987).
7. Scott, D. & Stevenson, D. J. Geophys. Res. 94, 2973–2988 (1989).
8. Forsyth, D. in Mantle Flow and Melt Generation at Mid-Ocean
Ridges (eds Phipps Morgan, J., Blackman, D. & Sinton, J.) 1–65
(American Geophys. Union, Washington DC, 1992).
9. Forsyth, D. et al. Science 280, 1215–1217 (1998).
10. Evans, R. et al. Science 286, 752–755 (1999).
11. Goldstein, S. J. et al. Nature 367, 157–159 (1994).
12. Perfit, M. et al. Geology 22, 357–397 (1994).
13. Perfit, M. & Chadwick, W. in Faulting and Magmatism at MidOcean Ridges (eds Buck, W. et al.) 59–115 (American Geophys.
Union, Washington DC, 1998).
Molecular motors
What makes ATP synthase spin?
Paul D. Boyer
any years ago, when enzymes were
first recognized as being proteins,
few people could have imagined the
wondrous, precise and diverse structures
that make possible their catalytic and other
functions. The ATP synthase enzyme, for
example, performs catalysis as a molecular
machine with an unexpected internal rotary
mechanism. On page 263 of this issue, Rastogi and Girvin1 report the latest insights into
this mechanism. Using sophisticated NMR
and chemical probes, they have revealed
structural changes in a critical subunit that
could drive the rotation.
ATP synthase, also known as F1F0 ATPase,
catalyses the formation of ATP (adenosine triphosphate) from ADP (adenosine
diphosphate) and Pi (inorganic phosphate),
in processes known as oxidative phosphorylation (driven by oxidations in animal cells
and microorganisms) and photophosphorylation (driven by light in plant cells). Once
formed, ATP is cleaved back to ADP and Pi, as
M
δ
α
α
β ATP
F1
g
b
b
2
γ ε
H+
H+ H+ H+
H+
c
c
aa
c
c
c
c
F0
Figure 1 Model of the Escherichia coli ATP
synthase. The enzyme consists of two parts
known as the F1 and F0 portions. The F1 portion
comprises three a subunits, three b subunits, an
e, d and g subunit. The F0 portion contains one a
subunit, one b subunit and 9–12 c subunits.
(Courtesy of R. L. Cross, State Univ. New York,
Syracuse.)
NATURE | VOL 402 | 18 NOVEMBER 1999 | www.nature.com
it provides the energy to drive a myriad of
metabolic processes including biosyntheses,
muscle contraction, and nerve and brain
function.
A model of the enzyme (Fig. 1) shows a
hydrophilic F1 portion above the F0 part,
which is embedded in a phospholipid bilayer membrane. The F1 portion from various
sources is made up of three a subunits, three
b subunits and one each of the g, d and e
subunits. The three catalytic sites are found
mainly on the b subunits. In the F0 portion
from the bacterium Escherichia coli, there
are one a subunit, two b subunits and 9–12 c
subunits. The F0 portion from various
plants and animals is more complex, but it
still contains the multiple copies of c-type
subunits.
As demonstrated by Peter Mitchell2,
energy from oxidation–reduction reactions
is captured by the formation of an electrochemical gradient of protons across the
membrane. This advance — and the growing
knowledge about proteins and the ATP synthase enzyme — provided the basis for a suggestion that I made a quarter of a century
ago3. The idea was that the protonation and
deprotonation of a carboxyl group in F0, as
protons cross the membrane, results in protein conformational changes coupled to the
formation of ATP. Rastogi and Girvin1 now
clothe this concept with reality.
Since this proposal, much has been
learned about the ATP synthase. The three
catalytic sites are known to pass sequentially
through three different conformations associated with substrate binding, formation of
tightly bound ATP, and release of the ATP.
These changes are thought to occur through
a rotational catalysis in which, as indicated in
Fig. 2 (overleaf), rotation of the g subunit
causes the requisite sequential changes in the
b subunits4.
The concept of a binding-change mechanism with rotational catalysis received
strong support five years ago when John
Walker’s group reported5 the X-ray structure
of the major portion of F1. This structure was
consistent with the idea that three different
conformations of the b subunits are interconverted by rotation of the g subunit. Avail© 1999 Macmillan Magazines Ltd
100 YEARS AGO
The authors of this research on the vibrations
of gun barrels were induced to make an
experimental investigation of the behaviour
of rifle barrels, in order to clear up certain
difficulties connected with that which is
known in ballistics as the error of departure.
It had been noticed that in shooting with a
rifle (whether loosely, or firmly fixed), that
the initial tangent to the trajectory — “die
Anfangstangente der Flugbahn” — does not
coincide, as would be expected, with the axis
of the bore of the barrel, when produced, but
is more or less inclined to it at a small angle;
this is called the angle of error of departure
... The collection of photo-chronographic
records, twenty-eight in number, show the
manner in which a rifle barrel vibrates when
subjected to the concussion due to an
explosive… The authors show that the
experimental results agree well with figures
calculated on the assumption that the rifle
barrel is a cylindrical tube.
From Nature 16 November 1899.
50 YEARS AGO
‘Data’
Nature of September 3 contained a letter
under this heading. In it Prof. A. V. Hill asks
that the word be used in its original sense,
that is, as the plural of datum, for which he
gives the “Oxford English Dictionary”
definition “A thing given or granted” and so
on. He adds that there may sometimes be an
excuse for regarding data as a collective
singular in the same way as agenda…. In
my view, the word ‘data’ has now come to
be generally accepted as having a wider
meaning than one based on its Latin
derivation. It is used, still as the plural of
datum, to indicate a collection of facts or,
more often, figures, and these may, indeed,
be regarded as ‘things given’ to the reader
for the argument or discussion based on
them. Changes in the meaning of a word are
common in a language that is still alive and
should, I suggest, be welcomed as a sign of
life. On the other hand, not even Prof. Hill
will convince me that one may deliberately
change the grammar of a word. ‘Data’ was a
plural noun; for literate English writers it still
is, and I contend that it always should be.
From Nature 19 November 1949.
Many more extracts like these can be found in
A Bedside Nature: Genius and Eccentricity in
Science, 1869–1953, a 266-page book edited by
Walter Gratzer. Contact Lisa O’Rourke.
e-mail: [email protected]
247