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well-established techniques for mani-pulating electron beams in a vacuum. Twodecades later the new field of mesoscopicphysics arose, in which pieces of metal orsemiconductor were made so small and coldthat the conduction electrons moved aroundin them as coherent waves. Fundamental tomesoscopic systems is the interferencebetween a host of different paths available toelectrons passing from one point to another.In a magnetic field the Aharonov–Bohmeffect should occur between every pair ofpossible paths, with important but generallyrather messy consequences, because thepaths are often very complicated and numer-ous.

It was predicted4 however that, for theparticular geometry of a small, thin-walledhollow metallic cylinder in an external mag-netic field (Fig. 1b), the Aharonov–Bohmeffect should cause the electrical conduc-tance to oscillate with the magnetic fluxthrough the cylinder’s bore. Whenresearchers evaporated a normal metal filmonto a two-micrometre-thick insulatingfibre they found exactly this behaviour5.Moreover, since then the Aharonov–Bohmeffect has become thoroughly established asa basic principle in the physics of mesoscopicsystems (many of which, incidentally, arecreated by drawing patterns with good oldelectron beams).

Nearly two decades further on, meso-scopic devices have now become ‘nanostruc-tures’, whose size scales reach down to themolecular level, and which sometimes evenemploy individual molecules at their heart.Rapidly becoming the archetype of these is aparticular class of wire-like molecules withextraordinary electrical properties — thecarbon nanotubes6. The simplest nanotubesare long, flexible, hollow cylinders, each likea drinking straw rolled from a single graphitelayer, where the atoms are arranged in ahexagonal lattice. Because these tubes are sonarrow (around 1.5 nm in diameter), elec-trons are quantum mechanically restrictedto move only parallel to the tube axis. Inthe past couple of years this has opened up areal-life laboratory for one-dimensionalphysics7,8, long the preserve of theorists.Another, more common type of nanotubecontains many coaxial graphitic cylinders.In these thicker (typically 10-nanometre ormore) multiwalled tubes, the electrons canmove relatively freely over the outer cylindri-cal surface — just the thing for observing theAharonov–Bohm effect.

Bachtold et al.1 attached metal leads toindividual multiwalled tubes, and foundconductance oscillations consistent with themetallic cylinder theory. Their results dra-matically demonstrate the potential for sci-ence in such nanostructures, where physicsand chemistry merge. The electron-beampaths in the Aharonov–Bohm experimenthave effectively been replaced by molecular

orbitals. Bachtold et al. were also surprised tofind extra oscillations with a smaller period,corresponding to electron paths that revolveseveral times around the cylinder beforeinterfering. Although there is no specificexplanation for these oscillations yet, theycould well represent the underlying nature ofthe orbitals in the nanotube, such as mightbe caused by a built-in twist in the graphitelattice. This illustrates the likelihood that,thanks to the infinitely rich nature of molec-ular orbitals, future molecular-scale experi-ments will lead to new science that goes farbeyond the domain of the old-fashionedmacroscopic laboratories.

It was not by coincidence that this seven-orders-of-magnitude reduction in the sizeof physics experiments came over the sameperiod that electric valves, arc lamps andcathode ray tubes were replaced by transis-tors, solid-state lasers and flat-panel dis-

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It might be misquoted of Hox genes that“in the field of development, never was somuch owed by so many tissues to so few

genes”. All animals have Hox genes, and themultifarious roles of Hox proteins in build-ing vital organs such as brain, muscle, boneand gut endow them with honorary statusamong the transcription factors, both incontrolling the fates of different cells and inarranging them into working structures.Valuable insights into how Hox proteinswork are offered by two new papers, oneby Passner et al.1 on page 714 of this issueand the other by Piper et al.2 in last week’sCell, which each describe the structure ofa Hox protein on its DNA-binding site incombination with a cofactor protein.

Over a century ago, Bateson3 describedhomeotic transformations as a change inone body part into the likeness of another,broad-mindedly including misplacedinsect appendages and transformations ofmammalian vertebrae. The vertebrae pat-tern switches were both anterior to posteriorand vice versa, which are the sorts of changesthat are now known to be caused by ectopicor by reduced Hox gene function.

Hox genes encode transcription factorsthat coordinate the expression of genes nec-essary for the implementation of differentdevelopmental pathways, so they can gener-ate some bizarre phenotypes when mutated:for example, Ultrabithorax mutations in thefruitfly Drosophila create an extra set ofwings, and Antennapedia mutants grow legsin place of antennae; in the nematodeCaenorhabditis elegans, Hox mutations re-route migrating cells; in mouse, they convertone type of vertebra into another or change

Development

Hox proteins reach out round DNAMatthew P. Scott

the pattern of hindbrain development; andin humans, they cause fusions and duplica-tions in hand and foot digits.

Hox genes are a specific subset of the hun-dreds of homeobox genes4. The homeobox isa 180-base-pair DNA sequence that encodesa 60-amino-acid DNA-binding domain, thehomeodomain. Hox genes are distinguishedfrom other homeobox genes both by theirmore closely related homeodomainsequences and by their clustered positions onchromosomes. Four clusters of mammalianHox genes, 39 genes in all, are thought to bederived from one ancestral cluster –– in flies,the single ancestral cluster evidently splitinto two parts. Within each fly or mam-malian cluster, Hox genes are convenientlyorganized according to the body region theyaffect: at one end of the cluster, genes arefound that are involved in anterior (head)development; at the other end, the geneswork for more posterior structures. Inbetween, genes are arranged roughly in theorder of their influence along the body, pro-ceeding from head to tail. Each mammaliancomplex is designated as A–D, and each genewithin the complex by a paralogue number,1–13: paralogue 1 genes act on the most ante-rior regions of the body axis, and paralogue13 genes on the most posterior ones. Genesthat have the same paralogue number butare located in different mammalian clustersare highly related and sometimes partiallyredundant in function.

The Ultrabithorax (Ubx) protein studiedby Passner et al.1 is produced and functionalin the posterior thoracic and anteriorabdominal segments of Drosophila5. Ubxmutations lead to posterior-to-central tho-

plays. The technology of nanostructures isdriven largely by the urge to make ever small-er and faster electronics9. However, scientistsare both pushing and riding the wave, andphysicists will be busy for a long whileexploring and exploiting their new nano-metre-sized laboratories.David H. Cobden is at The Niels Bohr Institute,University of Copenhagen, Universitetsparken 5,DK-2100 Copenhagen, Denmark.e-mail: cobden@fys.ku.dk1. Bachtold, A. et al. Nature 397, 673–675 (1999).

2. Aharonov, Y. & Bohm, D. Phys. Rev. 115, 485–491 (1959).

3. Chambers R. G. Phys. Rev. Lett. 5, 3–5 (1960).

4. Al’tshuler, B. L., Aronov, A. G. & Spivak, B. Z. JETP Lett. 33,

94–97 (1981).

5. Sharvin, D. Y. & Sharvin, Y. V. JETP Lett. 34, 273–275

(1982).

6. McEuen, P. L. Nature News & Views 393, 15–17 (1998).

7. Tans, S. J., Devoret, M. H., Groeneveld, R. J. A. & Dekker, C.

Nature 394, 761–764 (1998).

8. Bockrath, M. et al. Nature 397, 598–601 (1999).

9. Sohn, L. L. Nature News & Views 394, 131–132 (1998).

© 1999 Macmillan Magazines Ltd

order to impart greater DNA-bindingstrength and to hold helix-3 in an optimalcontact position for insertion of the hexa-peptide. In addition, the DNA is bent byabout 107 by both Pbx1 and HoxB-1, whichmay influence the strength of binding.

What are the implications of the featuresrevealed in these structures? First, Hox pro-teins of different paralogue groups associatein quite a similar way with Exd/Pbx proteins.Second, the basis for sequence specificity isnow clearer than when Hox proteins alonewere tested on DNA, but additional genuinetarget-gene cis-regulatory sequences need tobe identified before we can find out how thecombinatorial sequence recognition is actu-ally employed. Third, the different actions ofvarious paralogue groups could be accom-plished by association with proteins otherthan Exd/Pbx. Some paralogue groups havea hexapeptide sequence of Y/F-P-W-M-K/R(single-letter amino-acid code), whereasothers contain a tryptophan (W) residue in adifferent context4. Hexapeptides of differentparalogue groups have distinct sequences,paralogue groups have characteristic linkerlengths between hexapeptide and homeo-domain, and some paralogue groups havecharacteristic residues carboxy-terminal tothe homeodomain9. Each type of hexapep-tide could insert into a different cofactor ifmore proteins like Exd/Pbx exist. One candi-date is the Meis/Hth protein, a cofactor forExd/Pbx10–12. Alternatively, the linker lengthbetween the hexapeptide and the homeo-domain could affect which target-genesequence can be bound by the combinationof a Hox protein and Exd or Pbx. A stretched

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or distorted linker could alter the insertionorientation of the hexapeptide. Fourth, thesequence conservation found among someHox paralogues carboxy-terminal to thehomeodomain may indicate that suchregions have an indirect role in DNA bind-ing, as in the case of Pbx1.

Satisfaction comes from seeing universalsemerge, such as structural similaritiesbetween homeodomains and bacterialhelix–turn–helix proteins and yeast mating-type homeodomain proteins –– but at the same time, the new Hox–Exd/Pbx struc-tures are rich in novelty. Bateson would bepleased.Matthew P. Scott is in the Departments ofDevelopmental Biology and Genetics, HowardHughes Medical Institute, Stanford UniversitySchool of Medicine, Stanford, California 94305,USA. e-mail: scott@cmgm.stanford.edu

1. Passner, J. M., Ryoo, H. D., Shen, L., Mann, R. S. & Aggarwal,

A. K. Nature 397, 714–719 (1999).

2. Piper, D. E., Batchelor, A. H., Chang, C.-P., Cleary, M. L. &

Wolberger, C. Cell 96, 587–597 (1999).

3. Bateson, W. Materials for the Study of Variation (Macmillan,

London, 1894).

4. Duboule, D. Guidebook to the Homeobox Genes (Oxford Univ.

Press, 1994).

5. Lewis, E. B. Nature 276, 565–570 (1978).

6. Studer, M., Lumsden, A., Ariza-McNaughton, L., Bradley, A. &

Krumlauf, R. Nature 384, 630– 634 (1996).

7. Mann, R. S. & Chan, S. K. Trends Genet. 12, 258–262 (1996).

8. Popperl, H. et al. Cell 81, 1031–1042 (1995).

9. Sharkey, M., Graba, Y. & Scott, M. P. Trends Genet. 13, 145–151

(1997).

10.Chang, C. P. et al. Mol. Cell. Biol. 17, 5679–5687 (1997).

11.Rieckhof, G. E., Casares, F., Ryoo, H. D., Abu-Shaar, M. &

Mann, R. S. Cell 91, 171–183 (1997).

12.Berthelsen, J., Zappavigna, V., Ferretti, E., Mavilio, F. & Blasi, F.

EMBO J. 17, 1434–1445 (1998).

rax transformations, giving rise to Lewis’sfamous four-winged fly5, and to abdomen-to-thorax transformations. The humanHoxB-1 protein, the subject of the study byPiper et al.2, is required for normal develop-ment of rhombomere 4 of the hindbrain6,where hoxb-1 is expressed. hoxb-1 is mostrelated to the Drosophila ‘head’ gene labial,and is therefore in a different class from Ubx ,which is most closely related to Hox6–8.

Hox protein products of both Ubx andhoxb-1 interact functionally with anothergroup of homeodomain proteins calledExtradenticle (Exd) in flies and Pbx in mam-mals. These proteins enhance the specificityand affinity of DNA binding by Hoxproteins7. The pbx1 gene was first found atchromosome breakpoints associated withhuman leukaemia. Mutations in exd causediverse homeotic transformations, and yetexd does not transcriptionally regulate mostHox genes. Instead, Exd cooperates with Hoxproteins to bind to DNA, so loss of Exd func-tion leads to a compound phenotype incor-porating multiple Hox phenotypes. Simi-larly, Pbx1 has been found to cooperatewith Hox proteins in, for example,hoxb-1 autoregulation8. Thus, Exd/Pbx1proteins act as cofactors that increase theDNA-sequence specificity of Hox proteins.

The two new crystal structures that havebeen solved for the Ubx–Exd–DNA andHoxB-1–Pbx1–DNA complexes1,2 both dis-play the three a-helices that are characteris-tic of homeodomain structures. The DNAcontacts for Exd and Pbx1 differ from thoseof most homeodomains, however, and maybe weaker or less discriminating. The co-operative binding between the Hox andExd/Pbx1 proteins is due to a hexapeptideoutside and amino-terminal to the homeo-domain. The crystal structures reveal howthe individual components cooperate inbinding to one another: the two homeo-domains bind to opposite sides of the doublehelix of DNA. The Hox protein hexapeptide,which is on the end of a long linker arm,reaches around to Exd or Pbx1 on the otherside, inserting itself into a special pocket inExd or Pbx1 which is created partly by atripeptide loop peculiar to the Exd/Pbx1group of homeodomains. Because bothhomeodomains make sequence-specificcontacts with bases (sometimes the samebases) and with backbone atoms, the speci-ficity and binding affinity of the wholecomplex are enhanced.

Remarkably, a region of Pbx1 that is out-side the homeodomain on the carboxy-terminal side, and which is essential for thecooperative binding of Pbx1 and HoxB-1,does not touch either HoxB-1 or the DNA.Instead, it forms a fourth helix that packsagainst the third helix, which is the mostimportant determinant of sequence speci-ficity. This fourth helix is presumed to stabi-lize or modify the helix-3 configuration in

Bioenergetics

One price to run, swim or fly?R. McNeill Alexander

It has long been accepted that it is metaboli-cally cheaper for animals to fly than to run,and cheaper still for them to swim1.

Measurements of oxygen consumption haveshown, in comparisons between animals ofequal mass, that the energy used by a mam-mal to run one kilometre is enough to enablea bird to fly about two kilometres, or a fish toswim up to ten kilometres. But in a recentpaper in Philosophical Transactions of theRoyal Society, Williams2 repeats the analysisfor mammals alone and reaches the surpris-ing conclusion that their three types of loco-motion are almost equally priced. Thus, a100-kg seal needs as much energy to swim akilometre as a 100-kg pony would need to runa kilometre, and a 1-kg fruitbat needs onlya little less energy to fly a kilometre than amongoose of the same mass needs to run it2.

The energy cost of animal locomotion isexpressed as the cost of transport (energyused)/(body mass 2 distance travelled). It

may be defined either to include all the meta-bolic energy used on the journey (total costof transport) or only the extra energy,excluding that which would have been used ifthe animal had been resting (net cost).

Williams has compared total costs oftransport for marine mammals with differ-ent degrees of aquatic specialization, rangingfrom muskrats and sea otters, which havebodies and paws like those of their fully ter-restrial relatives, to sea lions with streamlinedbodies and flippers, and even whales, whichhave evolved tail flukes for efficient swim-ming. She finds that swimming is very expen-sive for semi-aquatic mammals: a 20-kg seaotter swimming at the surface uses five timesas much energy per kilometre as a sea lion ofthe same mass swimming under water. Forthis reason, semi-aquatic mammals are limit-ed to low speeds. Sea otters are slower than sealions, and dolphins are five times as fast, over50 metres, as world-record-holding human