Nature © Macmillan Publishers Ltd 1997

gap of solid hydrogen closes continuouslywith pressure, there comes a point at which itmay be energetically favourable to mix in asmall proportion of these ionic states, result-ing in a hybridized ground state. The pres-sure-induced electric dipole formed on anyone of these hydrogen molecules will interactwith, and be stabilized by, the other remain-ing molecules in the dense solid. Thestabilization of this new dipolar state will bepressure dependent, and so above a criticaldensity a spontaneous permanent electricpolarization sets in on each molecule (Fig. 3).

Edwards and Ashcroft calculate thenecessary conditions for the evolution of aninduced molecular dipole in hydrogen. Theypredict the appearance of a spontaneouselectronic polarization at a pressure where,experimentally, one sees the onset of thestriking infrared activity in hydrogen. Sodense hydrogen in phase III is composed ofmolecular, dipolar hydrogen. There may alsobe a reorientation and displacement of thedipolar molecules as the new, partly ionicstate of hydrogen forms.

But what of the anticipated transition tometallic hydrogen at even higher densities? Ithas been suggested that molecular hydrogenmay eventually become fully ionic, namelyH+H–, with enough compression6. But fromtheir calculations Edwards and Ashcroftfind that the system does not seem to beprogressing towards a fully ionic state.

What seems clear, however, is that thepresence of even partially ionic character inthe ground state of dense solid hydrogen willact to widen the previously narrowing bandgap and hence frustrate the transition to thelong-sought metallic state. Will solid hydro-gen ever become a metal? A pessimisticprospect, contrary to Bernal’s optimistic1926 generalization, might be that solidhydrogen may never achieve metallic status.

porting artiodactyl monophyly) and, if cor-rect, would make a cow or a hippopotamusmore closely related to a dolphin or a whalethan to a pig or a camel (Fig. 1).

Although it is compatible with earliermolecular analyses (for example, refs 4, 5),the idea that cetaceans are highly derivedartiodactyls was first suggested in 1994 onthe basis of mitochondrial and nuclear DNAand amino-acid sequences6. The idea wascorroborated by other phylogenetic analysesof DNA sequences7. But the issue is still con-troversial, because the exact means by whichmolecular sequence data should be analysedremains debated — although analytical set-tings that are particularly meaningful withrespect to phylogenetic inferences can prob-ably be identified in specific instances8. But,basically, many morphologists consider thatmolecular data are necessarily more noisythan morphological data.

The analyses by Shimamura and col-leagues now provide a remarkable exampleof molecular markers, which should lead

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622 NATURE | VOL 388 | 14 AUGUST 1997

Only time — and pressure — will tell.Peter P. Edwards is in the School of Chemistry, TheUniversity of Birmingham, Edgbaston, BirminghamB15 2TT, UK. Friedrich Hensel is in the FachbereichChemie, Philipps-Universität Marburg, D-35032Marburg, Germany.

1. Wigner, E. & Huntington, H. B. J. Chem. Phys. 3, 764–770 (1935).

2. Silvera, I. F. in Metal–Insulator Transitions Revisited (eds

Edwards, P. P. & Rao, C. N. R.) 21–42 (Taylor & Francis,

London, 1995).

3. Edwards, B. & Ashcroft, N. W. Nature 388, 652–655 (1997).

4. Mao, H.-K. & Hemley, R. J. Rev. Mod. Phys. 66, 671–692 (1994).

5. Ashcroft, N. W. Phys. World 8, 43–47 (1995).

Both morphological1 and molecular2

studies indicate that cetaceans(whales, dolphins and porpoises) and

artiodactyls (even-toed ungulates, whichinclude pigs, hippos, camels and ruminants)form a clade or monophyletic group — thatis, they have a common ancestor that is notshared by any other group of mammals. Thisis counter-intuitive, because it implies that acow is more closely related to a dolphin or awhale than to a horse, yet it is one of thebest examples of congruence betweenmorphological and molecular estimates ofmammalian phylogeny.

The molecular analyses of Shimamuraet al.3, reported on page 666 of this issue,further disrupt phylogenetic dogma.Indeed, not only do the authors confirm theclose relationship between artiodactyls andcetaceans, but they propose that cetaceansare deeply nested within the phylogenetictree of the artiodactyls. These results strik-ingly contradict the common interpretationof the available morphological data (sup-

Evolutionary biology

Even-toed fingerprints on whale ancestry Michel C. Milinkovitch and J. G. M. Thewissen

Figure 1 Twisted or untied? Shimamura et al.3 propose to attach the lineages of hippos and cetaceans(curved arrows, red) to the ruminant branch on this phylogenetic tree of artiodactyls — a markeddiversion from the traditional view (white branching pattern). The two smaller boxes summarizesome of the morphological evidence that disagrees with the new data.

Four-cusped bunodont teetLarge canine with triangular cross-section

Trochleated astragalusThree-lobed dP/4Supraorbital foramen

ParaxonyLacrimal extensive on faceIncrudal crus breve longThree bronchiPenile erection based on smooth muscle

Cetaceans (andmesonychians)

Ruminants Hippos andanthracotheroids

Pigs and peccaries

Camels and llamas

Other mammals

Figure 3 The newly predicted ground state ofmolecular hydrogen at ultra-high pressure3.Here the electron (charge) cloud preferentiallyaccumulates at just one of the two protons,producing an electric dipole. (The magnitude ofthis charge transfer has been exaggerated forclarity.) The inset shows molecular hydrogenunder normal conditions; here the two protonsare surrounded by a symmetrical charge cloud.

Nature © Macmillan Publishers Ltd 1997

morphologists to re-examine what mighthave misled them for more than a century.The authors report phylogenetic interpreta-tions of nine retropositional events that ledto the insertion of so-called ‘short inter-spersed elements’ at particular loci in thenuclear genome of various artiodactyl andcetacean ancestors. Three of these eventsunambiguously support the grouping ofcetaceans, hippos and ruminants in a clade,and the other six provide a partial resolutionof the relationships within that clade.Because the likelihood of these elementsbeing independently inserted at the samelocus in different lineages (or preciselyexcised) seems virtually nil, these markerscan reasonably be considered to be essen-tially noise-free.

So, these molecular results may prompt aserious revision of how we view morphol-ogical transformations in whales and artio-dactyls. Three salient features of artiodactylsare: first, the axis of symmetry of hand andfoot runs between the third and fourth digit(paraxony); second, the heel has developedan extremely mobile joint at a place wheremost mammals have a barely mobile joint9;and third, the last lower milk molar consistsof three rows of cusps (three-lobed deci-duous lower premolar 4, DP/4). Althoughparaxony is a striking feature, it also occurs inprimitive whales10, so it is uninformative forthe issue at hand. But the remodelled heel is adifferent matter — because it is present in allartiodactyls and in no other mammal, thischaracter is classically interpreted as derivedand, therefore, as supporting artiodactylmonophyly.

The presence of the mobile joint in artio-dactyls can be inferred from bones: there is apulley (or trochlea) on the distal part of theastragalus (one of the heel bones) — a so-called trochleated astragalar head. This led toefficient and fast locomotion in the earliestartiodactyls. Although some features of theartiodactyl heel are present in other mam-mals such as rabbits, the astragalar head isnever trochleated. In modern cetaceans, thehindlimb is so greatly reduced that the heelcannot be recognized, and no completefunctional astragalus is known for a fossilwhale. However, the mesonychians — agroup of land mammals that is considered tobe the closest extinct relative of cetaceans —also lack a trochleated astragalus. So if Shi-mamura and colleagues’ hypothesis is cor-rect, then either mesonychians are not close-ly related to cetaceans (and many dentalcharacters are convergent), or the specializedheel morphology is not the exclusive charac-ter that many morphologists take it to be. Itmay have evolved several times indepen-dently in artiodactyls, or have been lost in themesonychian/cetacean clade. The completeastragalus of an early cetacean wouldprobably shed light on this issue.

The hypothesis put forward by Shima-

mura et al. also clashes with the DP/4 charac-ter — the tooth has three lobes in allartiodactyls, but not in early cetaceans ormesonychians. If the new molecular data arecorrect, the morphology of this tooth has,like the trochleated astragalus, a complicatedphylogenetic history that includes reversals,convergences or both. Dental differencescould reflect dietary differences, becauseboth early cetaceans and mesonychians wereprobably carrion feeders or carnivores,whereas all early artiodactyls were omni-vores or herbivores. But many morphologi-cal systematists are reluctant to let functionalarguments influence their evaluation ofcharacters.

What characters, besides the molecularones described by Shimamura et al. and byGatesy7, do hippos, ruminants and cetaceanshave in common that makes them differentfrom pigs, peccaries and tylopods (camelsand llamas)? Morphological studies haveusually upheld close genealogical ties amongpigs, peccaries and hippos (and the largergroup that includes hippos: anthraco-theroids), but the similarities are usuallyuninformative primitive characters that arealso present in the ancestral artiodactyl, orfeatures that are subject to rampant conver-gences (such as certain dental characters, seeFig. 1). Shimamura et al. also suggest thatartiodactyls and cetaceans diverged in theCretaceous — about 15 million years beforethey are found in the fossil record. However,if hippos are closely related to cetaceans, andif mesonychians are not, then the discrepan-cy in the times of origin is considerably less: itamounts to the difference between the originof cetaceans (approximately 50 million yearsago) and that of anthracotheroids (around49 million years ago). But because of therapid and unique specialization of cetaceanmorphology, few characters can be recruitedto bolster the grouping of ruminants, hipposand cetaceans into a clade. Recovery andstudy of the earliest cetaceans wouldprobably help to resolve this problem.

Few molecular studies rule out previouslyaccepted morphological trees as convincinglyas that of Shimamura et al. However, the faceof phylogenetic science itself is changingrapidly — it is becoming more objective andless inductive. For example, phylogeneticistsno longer need to ask whether molecular dataare superior or inferior to morphologicaldata, because the signal-to-noise ratio in mor-phological, molecular and combined data setscan now be measured directly, even beforeexamining phylogenetic trees11. In any case,the new analyses indicate that the use ofretropositional events as molecular markersmay define a new power of resolution in esti-mating phylogenies. This method could evenbring to a close some of the most intense con-troversies2,12,13 in the field, such as whether thetoothed whales2,12 are monophyletic or para-phyletic, and likewise for the rodents13.

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NATURE | VOL 388 | 14 AUGUST 1997 623

100 YEARS AGO'Cyclone sail' — I have sent to you, forpublication, if you think desirable, aphotograph of a type of an ideal sail —ideal, in that the wind acting on it has notendency whatever to incline the boat. The wind pressure acts practically atright angles to the mean surface of thesail. When the wind is making a largeangle with the sail, the centre ofpressure is almost at the centre of thesurface, but when the wind strikes thesail at an acute angle, as in all sails orkites, the centre of pressure movestowards the weather edge; but bysuitably adjusting the sail, the desirableresult of obliterating all heelingmovement has been achieved. Percy S. PilcherFrom Nature 12 August 1897.

50 YEARS AGOOn June 6, 1942, there was a secondmeeting in Berlin, when the results of theuranium project were reported to Speer,as Minister for War Production. The factsreported were as follows: definite proofhad been obtained that the technicalutilization of atomic energy in a uraniumpile was possible. Moreover, it was to beexpected on theoretical grounds that anexplosive for atomic bombs could beproduced in such a pile.... Following thismeeting, which was decisive for theproject, Speer ruled that the work was togo forward as before on a comparativelysmall scale. Thus the only goal attainablewas the development of a uranium pileproducing energy as a prime mover — infact, future work was directed entirelytowards this one aim. Prof. W. HeisenbergFrom Nature 16 August 1947.

Many more abstracts like these can be found in A

Bedside Nature: Genius and Eccentricity in Science,

1869–1953, edited by Walter Gratzer. Contact David

Plant. e-mail: subscriptions@nature.com

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Michel C. Milinkovitch is in the Unit of EvolutionaryGenetics, Department of Molecular Biology, FreeUniversity of Brussels, cp 244, Boulevard dutriomphe, 1050 Brussels, Belgium.J. G. M. Thewissen is in the Department of Anatomy,Northeastern Ohio Universities, College of Medicine,PO Box 95, Rootstown, Ohio 44272-0095, USA.1. Thewissen, J. G. M.& Hussain, S. T. Nature 361, 444–445 (1993).

2. Milinkovitch, M. C. Trends Ecol. Evol. 10, 328–334 (1995).

3. Shimamura, M. et al. Nature 388, 666–670 (1997).

4. Irwin, D. M., Kocher, T. D. & Wilson, A. C. J. Mol. Evol. 32,

128–144 (1991).

5. Czelusniak, J. et al. Current Mammalogy Vol. 2 (ed. Genoways,

H. H.) 545–572 (Plenum, New York, 1990).

6. Graur, D. & Higgins, D. G. Mol. Biol. Evol. 11, 357–364 (1994).

7. Gatesy, J. Mol. Biol. Evol. 14, 537–543 (1997).

8. Milinkovitch, M. C. et al. Genetics 144, 1817–1833 (1996).

9. Schaeffer, B. Am. Mus. Novit. 1356, 1–24 (1947).

10.Thewissen, J. G. M., Madar, S. I. & Hussain, S. T. Cour.

Forschungsinst Senckenbg 191, 1–86 (1996).

11.Lyons-Weiler, J., Hoelzer, G. A. & Tausch, R. J. Mol. Biol. Evol.

13, 749–757 (1996).

12.Milinkovitch, M. C., Ortí, G. & Meyer, A. Nature 361, 346–348

(1993).

13.Hasegawa, M., Cao, Y., Adachi, J.& Taka-aki, Y. Nature 355, 595

(1992).

and differentiation of subtypes. At nano-molar concentrations, adenosine lowers theactivity of adenylyl cyclase (which convertsATP to cAMP) through adenosine A1 recep-tors, whereas micromolar levels augmentadenylyl-cyclase activity at A2 receptors5.

Xanthines and caffeine both blockadenosine receptors6, and this ability couldaccount for their effects as behaviouralstimulants. Xanthine derivatives can blockadenosine receptors in direct proportion totheir potencies as behavioural stimulants,and at concentrations similar to blood levelsof caffeine after a few cups of coffee7,8.The bronchodilating, antiasthmatic effectsof theophylline and other xanthines mayinvolve adenosine-receptor blockade,although the evidence is controversial.

Molecular-biological techniques havefurther discriminated receptor subtypes,specifically A1, A2a, A2b and A3 (ref. 9). The A2a

receptor (which stimulates adenylyl cyclase)is particularly abundant in the basal ganglia,blood vessels and platelets, so it was selectedby Ledent et al.1 for targeted deletion.

The A2a-receptor knockout mice seem to benormal on a gross level, and they breed suc-cessfully. But whereas the A2-agonist drugCGS-21680 reduces locomotor activity inwild-type mice, it has no behavioural effect inthe knockouts. Strikingly, caffeine, which nor-mally stimulates locomotor activity, substan-tially depresses activity in the knockout mice.These findings cement the conclusion that thestimulant effects of caffeine are derived fromadenosine-receptor blockade. But why shouldcaffeine depress behaviour in the knockouts?Adenosine analogues and caffeine can eitherstimulate or depress locomotor activity

depending on the dose7. So, in the knockouts, astimulatory action of adenosine — perhapsthrough A1 receptors — may be unmasked.

Ledent et al. also found that the knockoutmice seem to be more anxious and aggressivethan wild-type animals. This fits with abun-dant clinical evidence that caffeine increasesanxiety, and that stimulation of the adeno-sine receptor can relieve anxiety. Adenosinemodulates pain pathways in complex ways.There is evidence that stimulation of A2a

receptors on sensory pain fibres increasespain perception. The knockout mice showreduced pain responses, suggesting that — atleast at A2 receptors — adenosine normallyaugments pain perception. This also fits withobservations that caffeine can be analgesic.

Adenosine has many effects in the cardio-vascular system; it inhibits platelet aggre-gation and dilates several vascular beds. Theknockout mice show more efficient plateletaggregation than wild-type animals, andthey are resistant to inhibition of plateletaggregation by adenosine analogues. Ledentet al. also found that the knockout mice haveincreased blood pressure, supporting a tonicvasodilatory role for adenosine.

Pinning down the diverse biologicalfunctions of A2a receptors should provide aroute for the pharmaceutical industry todevelop related therapeutic agents (Table 1).One possibility might be new cognitivestimulants. Although the relative merits ofcaffeine’s stimulant effects are a source fordebate, its cognition-enhancing actions arewell documented. Agents that elicit thesebeneficial influences, without side-effectssuch as tachycardia, increased urination andagitation, may treat cognitive impairment ofthe elderly. At present, despite the wealth ofavailable analgesics, none is entirely satisfac-tory. Moreover, the complex effects ofadenosine on pain perception have thwartedefforts to develop adenosine-based anal-gesics10. The findings by Ledent et al.1 fromthe knockout mice favour selective A2a antag-onists as non-addictive analgesics. Finally,antagonists to the A2a receptor mightimprove defects in blood clotting andvascular shock, whereas A2 agonists shoulddecrease clotting and guard againstlow blood pressure.Solomon H. Snyder is in the Department ofNeuroscience, Johns Hopkins University School ofMedicine, 725 North Wolfe Street, Baltimore,Maryland 21205, USA.1. Ledent, C. et al. Nature 388, 674–678 (1997).

2. Burnstock, G. J. Physiol. (Lond.) 313, 1–35 (1981).

3. Braas, K. M., Newby, A. C., Wilson, V. S. & Snyder, S. H.

J. Neurosci. 6, 1952–1961 (1986).

4. Berne, R. M. Circ. Res. 46, 807–813 (1980).

5. Daly, J. W. Cyclic Nucleotides in the Nervous System (Plenum,

New York, 1977).

6. Satin, A. & Rall, T. W. Mol. Pharmacol. 6, 13–23 (1970).

7. Katims, J. J., Annau, Z. & Snyder, S. H. J. Pharmacol. Exp. Ther.

227, 167–173 (1983).

8. Fredholm, B. B. Pharmacol. Toxicol. 76, 93–101 (1995).

9. Olah, M. E. & Stiles, G. L. Annu. Rev. Pharmacol. Toxicol. 35,

581–606 (1995).

10.Sawynok, J. & Yaksh, T. L. Pharmacol. Rev. 45, 43–85 (1993).

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Over the past two decades, putativeneurotransmitters have proliferated,from biogenic amines to amino acids,

neuropeptides and, most recently, gases suchas nitric oxide and carbon monoxide. Amidstthe ferment over recently discovered messen-gers, scant attention has been paid to an atypi-cal neurotransmitter whose candidacy datesback almost 30 years — adenosine. But thefield may now be rejuvenated, thanks to areport by Ledent et al.1 (page 674 of this issue)showing that there are behavioural and physi-ological alterations in mice lacking oneadenosine-receptor subtype, A2a.

Neurotransmission by adenosine andATP — designated ‘purinergic’ byBurnstock2 — is difficult to study becauseboth molecules are involved in manypathways of general cellular metabolism.Nonetheless, the evidence for adenosine asa neurotransmitter is as persuasive as forany other substance: immunohistochemicalstudies have shown that adenosine is found indiscrete neuronal populations in which thosecells that use it as a neurotransmitter havemuch higher localized densities3; an efficient,energy-requiring uptake system exists whichcould account for synaptic inactivation ofadenosine; and adenosine has prominentfunctions outside the brain. Studies by Berne4

have shown that oxygen starvation leads to amassive accumulation of adenosine, whichcauses vasodilation and increased blood flow.

The most compelling evidence for thespecific actions of adenosine has come fromthe characterization of its receptors. Theinfluences of adenosine on levels of cyclicAMP in brain slices provided the first molec-ular evidence for the function of receptors

Adenosine receptors

Knockouts anxious for new therapySolomon H. Snyder

Table 1 Potential adenosine-receptor drug development based on the A2a knockout phenotype

Phenotype Drug

Altered locomotor response to caffeine A2 antagonists as cognition enhancers

Apparent anxiety A2 agonists as anxiolytics

Lesser pain responses A2 antagonists as analgesics

Increased platelet aggregation A2 agonists as anticoagulants;A2 antagonists for clotting defects

Hypertension A2 agonists as antihypertensives;A2 antagonists for shock