22.
1 N&V 299 MH 16/1/04 5:31 pm Page 301
development and in other organisms, where-
by mitotic progression is delayed if there are
defects in chromosome alignment during
metaphase.So,when Rogers et al. deactivated
KLP10A and KLP59C, the chromosomes
lined up abnormally — but compensatory
mechanisms were not engaged,and effects on
anaphase could still be assessed.
Another possible explanation is that
members of the Kin I family also control
other aspects of microtubule dynamics. So
inhibiting them can give rise to marked
structural defects in the spindle, producing
indirect effects on chromosome movements
and making it difficult to identify a specific
anaphase role for the motors. And, interest-
ingly, although functional characterization
of a vertebrate Kin I relative revealed ana-
phase defects9, detailed analysis indicated
that its primary role at the kinetochore is
to depolymerize incorrectly attached micro-
tubules, thus preventing the aberrant con-
nections that cause lagging chromosomes
and mis-segregation10. As multicellular
organisms that are more complex than fruit-
flies possess multiple Kin-I-related proteins,
it could be that the true functional counter-
parts of the anaphase fruitfly motors have yet
to be characterized.
What remains to be discovered? One
question is how microtubules maintain their
attachment to kinetochores and spindle
poles while undergoing polymerization
and depolymerization. Also, what do motile
motors at the kinetochore — such as dynein
and CENP-E — contribute to the process?
How are the multiple microtubules that attach
to a single chromatid coordinately regulated?
Mitosis provides a rich source of questions
for the mechanistically inquisitive. ■ 2. Rogers, G. et al. Nature 427, 364–370 (2004).
Rebecca W. Heald is in the Department of Molecular
Cell Biology, University of California at Berkeley,
Berkeley, California 94720-3200, USA.
e-mail: heald@socrates.berkeley.edu
1. Scholey, J. M. et al. Nature 422, 746–752 (2003).
Nanotechnology
Dreams of a hollow future
Luis Hueso and Neil Mathur
Carbon nanotubes have become familiar components in nanotechnology.
Nanotubes made from inorganic materials are now on the rise, the
latest creation being nanoscale tubes of a complex manganese oxide.
F
abricating small structures has long
been fashionable in physics. The
rationale is that reducing one or more
dimensions of a system below some key
length scale can change the system’s behav-
iour — carbon nanotubes are a good exam-
ple. But nanotubes made from other
materials are also proving useful for techno-
logical applications. In Applied Physics
Letters, Levy et al.1 add to the catalogue with
NATURE | VOL 427 | 22 JANUARY 2004 | www.nature.com/nature
©2004 Nature Publishing Group
news and views
a c
Metaphase 'Reeling in'
Chromosome Kinetochore
Tubulin
Centrosome
Kinetochore Spindle d
pole
'Pac-Man'
fibre
b
Anaphase
Figure 1 Achieving chromosome segregation in fruitfly cells. a, In metaphase, sister chromosomes are
already attached via their kinetochores to the plus ends of kinetochore fibres (bundles of microtubule
filaments), in the centre of the mitotic spindle. Sisters become aligned and oriented towards opposite
spindle poles, where microtubule minus ends are focused at centrosomes. b, In anaphase,
chromosomes move apart along kinetochore fibres, as the microtubules are depolymerized. c, d, Two
mechanisms of chromosome movement have been proposed, based on experiments in which a
marked segment (green) of the kinetochore fibre is tracked. c, In the ‘reeling-in’ mechanism4,5, the
minus end of the kinetochore fibre is depolymerized, while the chromosome maintains attachment at
the plus end. d, In the ‘Pac-Man’ mechanism6,7, the kinetochore fibre is chewed up from the plus end;
however, the chromosome remains attached and so moves polewards. Rogers et al.2 have discovered
that the motor protein KLP10A is behind the reeling-in mechanism, and KLP59C is the Pac-Man.
7. Gorbsky, G. J., Sammak, P. J. & Borisy, G. G. J. Cell Biol. 104,
3. Rieder, C. L. & Salmon, E. D. Trends Cell Biol. 8, 310–318 (1998). 9–18 (1987).
4. Mitchison, T. J. J. Cell Biol. 109, 637–652 (1989). 8. Desai, A., Verma, S., Mitchison, T. J. & Walczak, C. E. Cell 96,
5. Brust-Mascher, I. & Scholey, J. M. Mol. Cell. Biol. 13, 69–78 (1999).
3967–3975 (2002). 9. Maney, T. et al. J. Cell Biol. 142, 787–801 (1998).
6. Mitchison, T. J., Evans, L., Schulze, E. & Kirschner, M. Cell 45, 10. Kline-Smith, S. L., Khodjakov, A., Hergert, P. & Walczak, C. E.
515–527 (1986). Mol. Biol. Cell doi:10.1091/mbc.E03-08-0581 (2003).
physicists, where the conventional descrip-
tion of the electronic structure of three-
dimensional materials breaks down3. But
interesting effects are not restricted to
only the smallest nanotubes. Crude carbon-
nanotube structures, consisting of imper-
fectly concentric cylinders with diameters as
large as a few hundred nanometres, also have
technological uses. The high aspect ratio of
their report of the growth of nanotubes these structures means that electrons can be
made of a manganese oxide, namely a emitted easily from their tips. If these elec-
manganite. trons then traverse a vacuum and excite a
Carbon nanotubes, discovered by Ijima2 phosphor on a screen, this forms the basis of
in 1991, can be thought of as rolled-up sheets a display pixel. Indeed, proof-of-principle
of carbon atoms. The tubes have diameters displays using such multi-wall nanotube
as small as one nanometre, and are typically structures have been fabricated and promise
several micrometres long. Thus they are, to be ten times more energy efficient than
effectively, one-dimensional. This reduced competing plasma technology4.
dimensionality creates a new playground for The techniques of modern materials
301
©2004 Nature Publishing Group
22.1 N&V 299 MH 16/1/04 5:31 pm Page 303
science also allow the fabrication of inorganic
tubular nanostructures. As with the multi-
wall carbon nanotubes, no key length scales
are probed, but there is, again, the promise of
technological applications. Good examples
are the piezoelectric nanotubes made from
complex oxides such as barium titanate5,6 and
strontium–bismuth tantalate7.‘Piezoelectric’
means that these polycrystalline tubes can be
strained when an electrical voltage is applied,
and vice versa. Each tube could be triggered
individually to release a small quantity of ink
for ink-jet printing, or to deliver drugs into a
patient. Sensor, actuator and data-storage
applications are also possible.
The excitement generated by piezoelec-
tric nanotubes has now inspired Levy et al.1
to emulate the same growth technique using
a different and resurgent class of oxides.
Manganites are complex oxides that adopt a
pseudo-cubic perovskite crystal structure.
Half a century ago, it was found that an
applied magnetic field could significantly
change the electrical resistance of these
materials8, but it is only in the past decade
that these ‘magnetoresistance’ effects have
been studied in detail. The catalyst for
this activity was the discovery of colossal
magnetoresistance in a thin film9, just as
thin-film magnetoresistance effects were
making the transition from the laboratory
to application in read heads for computer
disk drives.
To fabricate their nanotubes of lantha-
num–praseodymium–calcium manganite,
Levy et al. first made a porous template by
chemically etching films of mylar and poly-
carbonate that had been bombarded with
heavy ions. They then introduced a precursor
solution into the (wetted) pores, and
achieved crystallization by heating the tem-
plate.Microstructures comprising long,thin-
walled nanotubes formed spontaneously
(Fig. 1). Through various structural charac-
terization techniques, Levy et al. confirmed
NATURE | VOL 427 | 22 JANUARY 2004 | www.nature.com/nature
©2004 Nature Publishing Group
Figure 1 Going
inorganic. Levy and
colleagues1 made
these inorganic
nanotubes from
lanthanum–
praseodymium–
calcium manganite.
The changing
electrical resistance
of this material in a
magnetic field
suggests that such
nanotubes could
be usefully applied
in nanotechnological
devices, such as
fuel cells.
that each tube is composed of manganite
nanocrystals. Moreover, rough estimates of
the magnetic properties match those expected
for bulk samples of this manganite.
How might manganite nanotubes impact
on technology? One possible application is
in solid-oxide fuel cells. A fuel cell differs
from a battery in that reactants may be con-
tinuously fed into it and exhausted. The
microstructure demonstrated by Levy et al.
immediately suggests a means by which
gases may be efficiently distributed in such a
cell. And as manganites conduct both elec-
trons and oxygen ions, and are resistant to
high-temperature oxidizing environments,
they make good cathodes.
More speculatively, nanotubes made
from metallic manganites could act as highly
localized sources of electrons possessing
spins of a particular orientation. This is
possible because the spins of the conduction
electrons in manganites can be aligned per-
fectly, whereas in ordinary magnetic metals
such as cobalt the alignment is only partial.
It is possible to imagine the nanoscale engi-
neering of electronic circuits in which the
spin of electrons, as well as their charge,
could be manipulated with precision —
a valuable capability for spin-sensitive
scanning probe microscopy, and perhaps,
ultimately, quantum computing.
Nanotube structures may also offer a
means of tuning the strong interactions that
exist between the magnetic, electronic and
crystal structures of a manganite. These
interactions generate rich phase-coexistence
phenomena over a wide range of length
scales, as has been revealed by imaging meth-
ods10. For example, a ferromagnetic metallic
phase may coexist with an antiferromagnetic
insulating phase. In a nanotube, the delicate
balance between the diverse phases could
be tuned readily through the stresses associ-
ated with the unconventional geometry.
Exploring the parameter space of chemical
©2004 Nature Publishing Group
news and views
100 YEARS AGO
Elementary Physiology and Hygiene. This
book has obviously been written to supply
the wants of the American schoolchild, and
consequently “the subject of alcohol has
been treated very thoroughly and in full
compliance with the laws of the various
States.” “Throughout the book the effects
of alcohol and other narcotics have been
discussed in close connection with the
accounts of the functions of the body.” The
above quotations from the author’s preface
show that it has been a pleasure to him to
comply in his book with the law enjoining
that all text-books of physiology used in
American State schools must contain a
description of the effects of alcohol on the
body. So thoroughly has this instruction
been carried out that it appears on reading
the book as if in many cases the very brief
descriptions of the physiology of the
different tissues had been written chiefly as
introductions in order to make clear the dire
effects of alcohol, which are subsequently
described in each case… Truly this book
must be appalling reading to the American
schoolchild whose parents may be in the
habit of making even moderate use of
alcoholic drinks.
From Nature 21 January 1904.
50 YEARS AGO
For the Seventh Arthur Stanley Eddington
Memorial Lecture… Prof H. H. Price,
Wykeham professor of logic in the University
of Oxford, spoke on “Some Aspects of the
Conflict between Science and Religion”…
Prof. Price argues that of late the main
conflict between science and religion has
been over two opposed conceptions of
human personality, a materialist and a
dualist one. On one side, it is held that all
mental processes are produced by and
inseparable from bodily processes, or else
actually are bodily. According to the
religious conception, on the other side, some
kind of cognition of the divine is possible,
which cannot be supposed to have any
ordinary physiological correlates, and also
some kind of other-worldly existence
distinct from the present bodily one. The
systematic investigation of the phenomena
of para-normal cognition, such as telepathy,
clairvoyance and precognition, has made the
materialist conception far less plausible, if
not untenable. A dualist type of theory… can
no longer be dismissed as unscientific and
superstitious.
From Nature 23 January 1954.
303
22.1 N&V 299 MH 16/1/04 5:31 pm Page 304
news and views
composition, grain size, tube dimensions
and tube distribution should reveal more
exciting possibilities ahead. The future of
nanotubes looks anything but hollow. ■ 4. Amaratunga, G. IEEE Spectrum 40, 28–32 (2003).
Luis Hueso and Neil Mathur are in the Department
of Materials Science and Metallurgy, University of
Cambridge, New Museums Site, Pembroke Street,
Cambridge CB2 3QZ, UK.
e-mails: leh29@cam.ac.uk
ndm12@cus.cam.ac.uk
Psychology
Insight and the sleep committee
Pierre Maquet and Perrine Ruby
We all spend about a third of our lives asleep, an essential but
seemingly unproductive state. Experimental evidence now emerges to
support anecdotal evidence that sleep can stimulate creative thinking.
D
oes this experience seem familiar?
The solution to an unfathomable
problem, left unresolved in the
evening, effortlessly pops into your mind the
following morning. Although many people
believe that sleep plays a role in these flashes
of insight, this is a hypothesis that has not
been rigorously tested. On page 352 of this
issue1, however, Wagner and collaborators
provide evidence that sleep can have a
beneficial effect on insight.
The authors have applied a clever test
that allows them to determine exactly when
insight occurs in the time course of learning2.
ALFRED PASIEKA/SPL
SPL
CORBIS
Figure 1 Instances of insight and creativity said to have followed sleep (or rather, except in the case of
Massenet, occurring during or following a dream). Some may be apocryphal. But these examples
foster the general feeling, tested in a controlled manner by Wagner et al.1, that sleep may aid insight.
304
©2004 Nature Publishing Group
1. Levy, P., Leyva, A. G., Troiani, H. E. & Sánchez, R. D. Appl. Phys.
Lett. 83, 5247–5249 (2003).
2. Ijima, S. Nature 354, 56–58 (1991).
3. Ishii, H. et al. Nature 426, 540–544 (2003).
5. Hernandez, B. A. et al. Chem. Mater. 14, 480–482 (2002).
6. Luo, Y. et al. Appl. Phys. Lett. 83, 440–442 (2003).
7. Morrison, F. D., Ramsay, L. & Scott, J. F. J. Phys. Condens. Matter
15, L527–L532 (2003).
8. Volger, J. Physica 20, 49–54 (1954).
9. Jin, S. et al. Science 264, 413–415 (1994).
10. Mathur, N. & Littlewood, P. Physics Today 56, 25–30 (2003).
In this task, the participants have to trans-
form a string of eight digits into a new string,
the last digit of which is the final solution
(see Fig. 1 on page 353). To do this, they are
instructed to apply two simple rules sequen-
tially, from one digit to the next. However,
unknown to the subjects, another rule is hid-
den in the material: the last three responses
mirror the three preceding ones.Discovering
the hidden rule can speed up the execution of
the task, as the final solution is known when
the third digit is specified.
All participants were trained in the task
(three blocks of tasks), then retested (for ten
NATURE | VOL 427 | 22 JANUARY 2004 | www.nature.com/nature
©2004 Nature Publishing Group
blocks) after eight hours. During the eight-
hour period the subjects were either awake
(during daytime or during the night) or
sleeping. When they were retested, the pro-
portion who gained insight in those allowed
to sleep (60%) was more than twice that in
those who remained awake (22%). If sub-
jects were exposed to the task continuously
for 13 blocks, without having been trained
the day before, the proportion who gained
insight was similar to that in the awake
groups. In other words, the favourable effect
of sleep on insight occurred only if a memory
had been formed before the sleep period.
The data further suggest that the con-
scious use of the hidden rule did not evolve
from procedural learning — that is, from the
unconscious acquisition of a skill through
practice. Rather, it stemmed from separate
mental representations that were rearranged
during sleep after training had taken place.
First, although in the sleep group the times
taken to solve each sequence of the string of
digits decreased overnight in both ‘solvers’
(the 60% who gained insight later on) and
‘nonsolvers’ (who did not), this overnight
decrease in reaction time was much smaller
in the solvers than in the nonsolvers. Second,
compared with the nonsolvers,the responses
to the first digits in a sequence were delayed
in the solvers as early as the end of the train-
ing session. It seems that the solvers spent
time analysing the task during the training
and retest sessions. Nevertheless, the solvers
were the fastest to find the final solution in a
sequence because they were aware of and
applied the hidden rule.
The primitive elements of the task that the
participants gleaned during training seem to
MGM/THE KOBAL COLLECTION
have been reorganized during sleep, eventu-
ally leading them to become conscious of the
hidden rule the following morning. Sleep has
been implicated in learning and memory in
the adult brain and is thought to favour
the ‘off-line’ processing of new memories3.
Wagner and colleagues’ data can be viewed
as an extreme case of memory processing, in
which the reorganization of primitive repre-
sentations leads to a new conscious knowl- MARY EVANS PICTURE LIBRARY
edge that entirely changes and improves the
subject’s ability to crack the problem.
This study, of course, raises plenty of
questions. What are the neural correlates of
the processing of the primitive representa-
tions during sleep that lead to the gain of
insight the following day? During wakeful-
ness, learning of the hidden rule is known to
be related to activation of two parts of the
brain in particular — the perirhinal cortex
and superior parietal lobule2. Do these areas
participate in the off-line processing during
sleep? What are the neuronal interactions,
reinforced during sleep, that underpin the
emergence of the conscious knowledge?
There is also the issue of whether all
stages of sleep participate in these processes
— that is,what does the ‘sleep committee’that
5.2 N&V 493 MH 30/1/04 5:41 pm Page 500
news and views
solute transporters. In this last model, ele-
gant in its minimalism, voltage dependence
arises not from movement of the gating
charges through the transmembrane electric
field, but from the field moving around the
charges. The mobile-S4 models rest on evi-
dence variously supporting transmembrane
motion on the order of 10–20 Å (refs 3, 4),
whereas the transporter picture puts much
weight on fluorescence experiments8 indi-
cating that S4 moves less than 2 Å.
A paroxysm of recent papers9–12 has
examined the proximity of residues near the
external end of S4 to the pore domain. On
channel opening, the extracellular ends of S4
and S5 come close together,and although this
finding fails to distinguish among the three
classes of model, it does constrain their indi-
vidual depictions of the ‘out’ state. Pictures
of the ‘in’ state are even murkier. The X-ray
structure5 shows S4 in an intracellular posi-
tion, but this structure, which everyone
acknowledges is distorted by crystal-packing
forces, is unrepresentative of the S1–S4
domain in a membrane. Nevertheless, elec-
trophysiological studies4,6 place part of the ‘in’
paddle near the inside solution. In contrast, a
tarantula-venom peptide binds preferentially
to the ‘in’ state of a Kv channel, using receptor
determinants on the extracellular ends of S3
and S4 (ref. 13); because the peptide inhibits
from the outside, this result would rule out
the paddle model if it were established that
the toxin encounters its receptor directly from
aqueous solution,rather than from within the
membrane.But that’s a big ‘if’.
Against this ambiguous background,
Starace and Bezanilla1 reveal a surprising
property of the ‘in’ configuration of S4: pro-
ton conduction. Mutation of the outermost
S4 arginine to histidine produces a steady
transmembrane leak of protons. This con-
ductance behaves as though it is specifically
S1 S2 S3 S4 S5 S6 Membrane
Figure 1 Composition of one subunit of a
voltage-dependent K+ channel. A channel
consists of four subunits, parts of which
together form a central pore, and each subunit
consists of six membrane-crossing -helices,
S1–S6. S5 and S6 are the ‘pore domain’ (a
subunit’s contribution to the pore). S1–S4 are
the ‘gating domain’. It is charged amino acids
on S4 that are mainly responsible for voltage
sensing, and movement of S4 that is the
principal bone of contention.
500
mediated by the introduced histidine side
chain, and most importantly it is present
only for the voltage sensor’s ‘in’ state. The
authors estimate a unitary turnover rate
of some 50,000 protons per second, and
conclude that this high value implies that the
histidine side chain is exposed to aqueous
solution on both sides of the membrane
simultaneously. From this they draw several
structural inferences: that the ‘in’ state of the
voltage sensor allows the two solutions to
approach perilously close to each other, such
that protons can access the side chain from
both sides, and that the transmembrane
voltage therefore falls across an exceedingly
short distance (that of a single side chain).
Declaring the paddle model inconsistent
with such a picture, Starace and Bezanilla
assert that voltage-sensor movement is
transporter-like, as in Fig. 2c, with the outer-
most S4 position acting as a narrow ‘gate’that
separates internal and external solutions in
the ‘in’state.
In our view, though, it is too big a step to
translate proton conductance into a unique
structural image of the voltage sensor.A pro-
ton leak does not necessarily imply direct
access from bulk aqueous solutions; an alter-
native possibility would be that the histidine
residue connects to solvent via narrow
crevices formed from protonatable protein
groups and individual water molecules.Such
pathways could act as proton conduits to the
histidine side chain, as seen in proteins con-
taining ‘proton wires’as long as 15 Å (ref.14).
The distance separating the two bulk solu-
tions could be further lengthened by about
7 Å if proton transport were also mediated
by a histidine side-chain flip. Thus, the sepa-
ration of internal from external solutions
need not be unusually narrow. We agree that
the proton current described by Starace
and Bezanilla rules out a paddle completely
surrounded by bilayer lipid, but a paddle in
contact with the pore domain could still be
consistent with these observations.
Stepping back from the fray, we should
not forget that broad agreement prevails
on basic issues of voltage sensing, and
that the current controversy is really about
fine details at the level of protein chemistry.
The jury, we think, is still out, and before
a firm choice of model can be made we’ll
need to see more experiments — and more
structures. ■ J. K. J. Mol. Biol. 291, 899–911 (1999).
Robert O. Blaustein is in the Molecular Cardiology
Research Institute, Tufts-New England Medical
Center and Department of Neuroscience,
Tufts Medical School, 750 Washington Street,
Boston, Massachusetts 02111, USA.
e-mail: robert.blaustein@tufts.edu
Christopher Miller is in the Department
of Biochemistry, Howard Hughes Medical
Institute, Brandeis University, Waltham,
Massachusetts 02454, USA.
e-mail: cmiller@brandeis.edu
1. Starace, D. M. & Bezanilla, F. Nature 427, 548–553 (2004).
NATURE | VOL 427 | 5 FEBRUARY 2004 | www.nature.com/nature
©2004 Nature Publishing Group
a
In Out
Pore
Voltage
change
b
c
Figure 2 Models of voltage-sensor behaviour;
the voltage sensors’ change from the ‘in’ to the
‘out’ position triggers pore opening. a, The
sliding-helix and, b, paddle models. These two
diagrams show the four subunits, with the
voltage-sensing components of each depicted
in green. c, The transporter-like model proposed
by Starace and Bezanilla1, based on mutation
of the outermost S4 amino acid from arginine
to histidine (red circle), and depicted in a
single subunit. According to this view of events,
in its ‘in’ position the voltage sensor separates
the internal and external solutions with a
narrow gate that produces a highly focused
electric field.
2. Yellen, G. Nature 419, 35–42 (2002).
3. Yang, N., George, A. L. & Horn, R. Neuron 16, 113–122 (1996).
4. Larsson, H. P., Baker, O. S., Dhillon, D. S. & Isacoff, E. Y. Neuron
16, 387–397 (1996).
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Correction
In “Dreams of a hollow future” by Luis Hueso
and Neil Mathur (Nature 427, 301–304; 2004),
the third sentence of the figure caption was
added in error by an editorial hand: the property
of magnetoresistance in manganites has no
connection to fuel-cell technology.