but ‘off ’ to produce the trunk. Yet we knowthat all three growth factors act in a concen-tration-dependent fashion during early axisformation. A gradient of Nodal proteininstructs cells at different points along thegradient to take on different mesodermalfates; this then translates into an increasingdorsal-to-ventral gradient of BMP7,8 and anincreasing head-to-tail gradient of Wnt9,generating a continuum of positional infor-mation. Completely blocking Wnt inhibitstrunk formation, so trunk-organizer activitymust require some — probably low levels of— Wnt signalling, rather than the completeinhibition suggested by the authors.

Second, unlike BMPs and Wnts, Nodalproteins affect the head-to-tail patterning of neural tissue only indirectly, inducingmesendodermal tissue to produce, forinstance, Wnts, Wnt inhibitors and BMPinhibitors at different threshold activities ofNodal. A model complementary to that ofAgathon et al. focuses on the more directplayers — BMP and Wnt — in regulatingaxis formation (Fig. 1b), and takes intoaccount their activity gradients.

Finally, how does the tail organizeruncovered by Agathon et al. interact with theSpemann organizer to induce complete tails?And how can we integrate the process oftrunk ‘segmentation’, which is controlledfrom the tail bud? Whatever the answers, thenew work1 should generate greater interest inquestions relating to the tail. ■

Christof Niehrs is in the Division of MolecularEmbryology, Deutsches Krebsforschungszentrum,Im Neuenheimer Feld 280, 69120 Heidelberg,Germany.e-mail: niehrs@dkfz-heidelberg.de1. Agathon, A., Thisse, C. & Thisse, B. Nature 424, 448–452

(2003).

2. Harland, R. M. & Gerhart, J. Annu. Rev. Dev. Biol. 13, 611–667

(1997).

3. Mangold, O. Naturwissenschaften 21, 761–766 (1933).

4. Piccolo, S. et al. Nature 397, 707–710 (1999).

5. Beck, C. W. & Slack, J. M. Development 126, 1611–1620 (1999).

6. Beck, C. W., Whitman, M. & Slack, J. M. Dev. Biol. 238, 303–314

(2001).

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Nature Rev. Genet. 1, 171–181 (2000).

8. Schier, A. F. Curr. Opin. Genet. Dev. 11, 393–404 (2001).

9. Kiecker, C. & Niehrs, C. Development 128, 4189–4201 (2001).

10.Gilbert, S. F. Developmental Biology 7th edn (Sinauer,

Sunderland, Massachusetts, 2000).

11.Gilbert, S. F. & Saxen, L. Mech. Dev. 41, 73–89 (1993).

to be formed from just three quarks. In addi-tion, QCD seems to allow more complicatedclusters of quarks or anti-quarks — atomicnuclei are familiar examples of quarks boundin multiples of three. An open question iswhether there are analogues containing anti-quarks. The simplest would be two quarksbalanced by two anti-quarks, in effect a ‘mol-ecule’ of two conventional mesons, or threequarks accompanied by an additional quarkand an anti-quark,making a pentaquark.

Unambiguous evidence for such states inthe data is lacking. Their absence is attrib-uted to the ease with which they would fallapart into a pair of conventional mesons,or ameson and a baryon. It is estimated that theywould survive for less than 10124 seconds,which is at the current limit of detection.But the sightings of the three metastable

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376 NATURE | VOL 424 | 24 JULY 2003 | www.nature.com/nature

Particle physics

Strange daysFrank Close

Three new subatomic particles have been found, and all survive for anunusually long time before they decay. Physicists now face thechallenge of explaining this within the framework of the existing theory.

“It is as if Cleopatra had fallen fromher barge in BC and had not yet hitthe water.” Such was the description

half a century ago of the discovery of theastonishingly long lifetime (up to about1018 seconds) of strange particles. Everydaymatter, such as protons and neutrons, ismade of two types of quark, known as ‘up’and ‘down’ (Fig. 1). But in 1947, new parti-cles were discovered that contained a thirdtype of quark, called ‘strange’1. Today,strange particles are a well-established partof the standard model of particle physics,which now includes six types of quark. Weknow that their seemingly long lifetimes area consequence of the ‘weak’ interaction thatthey undergo in decaying: if instead theywere subject to the powerful ‘strong’ inter-action their lives would be over in around10123 seconds. Instead, death by decay isneutered by the presence of strangeness.

In the past two months, three differentparticles have been discovered, and explain-ing them has proved a challenge for theorists.Although not as extreme as the above exam-ple,each of these new particles has an unusu-ally elongated lifetime. Two of them are‘mesons’, each containing a strange anti-quark and a charm quark (the fourth quark

type)2,3. The reason for their metastability isunderstood, but their detailed nature anddynamics remain to be resolved. The thirdparticle4 is a member of the ‘baryon’family ofparticles that also includes the proton andneutron.But,unlike the proton and neutron,this particle has some strange-quark con-tent. In fact, unlike any other baryon known,it has overall one unit of ‘positive strange-ness’. It is an enigma. The quark model thatnow underpins the standard model wasdeveloped, in part, under the assumptionthat such things do not exist.And although itmay be possible to interpret this particle as acombination of four quarks (two up, twodown) and a strange anti-quark (providingthat unit of positive strangeness), the chal-lenge is to explain also why this ‘pentaquark’does not fall apart more quickly.

Viewed at high resolution (through high-energy particle collisions), mesons andbaryons appear to be swarms of quarks,anti-quarks and gluons — the quantum bundlesthat glue these constituents to one another,according to the theory of quantum chromo-dynamics (QCD). At lower resolution, thepicture is simpler. The mesons and baryonsform two distinct classes: mesons consist of asingle quark and anti-quark; baryons seem

Up/anti-up

Down/anti-down

Strange

Bottom

Charm

Top

Proton

Proton Neutron

New meson? New baryon?

K+

Deuteron

Meson Baryon

Quarks

Figure 1 Quarks and particles. In the standardmodel of particle physics, there are six quarks —fundamental particles that are the building-blocks of many others. Each quark also has ananti-matter partner, an anti-quark. Pairings ofquarks and anti-quarks form ‘mesons’, such as theK&; three quarks form ‘baryons’, such as theproton. The picture builds up further: a three-quark proton and a three-quark neutron togetherform a deuteron; adding more protons andneutrons — more three-quark combinations —builds up atomic nuclei. The discoveries of whatseem to be a new meson2,3 and a new baryon4

don’t easily fit the established picture. The newmeson may in fact be a ‘molecule’ of two mesons,and the baryon might be a ‘pentaquark’ state.

© 2003 Nature Publishing Group

particles, reported by the BaBar2 and CLEO3

experiments in the United States and theSPring-8 experiment4 in Japan,may at last beproof of these states’existence.

The baryon is utterly novel. In 60 years ofstudying strange particles,no such combina-tion of electrical charge and strangeness (onepositive unit of each) with baryon nature hasbeen seen. The original sighting in Japan hasbeen corroborated by two other experi-ments5,6, but all of the detections are at levelsthat are currently on the borderline of signif-icance, limited by the amount of data avail-able.The simplest response is to wish it away.But within the next year a high-statisticsexperiment is planned to establish whether itreally exists and, if so, to measure its proper-ties (such as its spin). If it is real, then it maybe most naturally explained as a pentaquark,containing a strange anti-quark. Its meta-stability would require that it is one of a family of particles related through a propertycalled ‘isospin’. Because isospin must be con-served (in the same way that, for example,energy and momentum must be conservedwhen billiard balls collide), the number ofways in which these particles can decay isrestricted, and so they cannot decay quickly.If this picture is correct, it implies the exis-tence of more of these baryons with unusualcorrelations of charge and strangeness, andthey could be searched for in moderatelyhigh-energy experiments.

By contrast, there is no doubt about theexistence of the two meson states, bothknown as ‘DS’. They appear as clear peaks inthe data and their spins almost certainly havethe values zero and one (thus they arereferred to as ‘scalar’ and ‘axial’ mesons,respectively). They have all the characteris-tics of states made from a charm quark and astrange anti-quark, but, for some reason,

have masses that are lower than expected —so much lower, in fact, that their naturaldecay paths (into a charm meson and astrange meson) are energetically closed.Thisis the cause of their metastability. But thequestion of why they are so much lighterthan their siblings in the charm–strangefamily is still to be resolved.

One possibility is that they are betterdescribed as ‘molecules’ — bound states ofmesons, one containing a charm quark andthe other a strange quark, with energiesslightly below the fall-apart threshold.This isanalogous to a proton and a neutron bindingtogether to form a deuteron,and such behav-iour has been seen elsewhere for scalar (spinzero) mesons. The masses of the newly dis-covered mesons are tantalizingly close to thethresholds for some two-meson states (in thecase of the scalar meson, a molecule of a Kand a D meson; and in the case of the axialmeson, of a K and a D* meson). It seems certain that these meson combinations playsome role in lowering the observed masses ofthese new-found particles.

Further ways of producing these enigmatic states, along with more precisemeasurement of their properties, are nowbeing pursued to identify the sources of theirunexpected longevity. ■

Frank Close is in the Department of TheoreticalPhysics, University of Oxford, Keble Road,Oxford OX1 3NP, UK.e-mail: f.close1@physics.ox.ac.uk

1. Rochester, G. D. & Butler, C. C. Nature 160, 855–857 (1947).

2. Aubert, B. et al. Phys. Rev. Lett. 90, 242001 (2003).

3. Besson, D. et al. Preprint at <http://arXiv.org/hep-ex/0305100>

(2003).

4. Nakano, T. et al. Phys. Rev. Lett. 91, 012002 (2003).

5. Barmin, V. V. et al. Preprint at <http://arXiv.org/

hep-ex/0304040> (2003).

6. Stepanyan, S. et al. Preprint at <http://arXiv.org/

hep-ex/0307018> (2003).

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NATURE | VOL 424 | 24 JULY 2003 | www.nature.com/nature 377

monkey was placed in front of a computerscreen, and each trial started with the animalfixating on a central spot for 0.3 seconds.Themonkey, continuing to fixate, was then pre-sented with four identical visual targetssimultaneously, superimposed for half a second on a complex, coloured visual scene.The background scene, but not the four targets, then disappeared, and after a delay of 0.7 seconds the fixation spot also disap-peared, cueing the animal to move its eyestowards one of the targets. Only one of thesetargets was associated with a reward — asquirt of fruit juice. An experienced monkeyrequired about a dozen trials to learn the cor-rect position of the rewarded target in eachnew scene. On their road to fame, the twomonkeys involved in this study saw a total of378 new scenes over the course of 18 months,of which they learned 290 as required.

And as the monkeys’ eye muscles workedfor the juice, so too did the neurons in theirhippocampus. Wirth et al. recorded the elec-trical activity of these neurons in order to geta handle on their role in learning. This wasmade feasible by the fact that the associativetask is,on the one hand,not too easy, so that ittakes a monkey some time to master it —enough time for the experimenter to followneuronal dynamics.On the other hand,how-ever, the task is not too difficult,meaning thatthe monkey can still succeed while the experi-menter ‘holds’ a given nerve cell (in practice,not more than 30 to 50 minutes). So this is an example of cross-level analysis, tappinginto behavioural and cellular processes con-currently — virtually essential for studiesthat aim to analyse the biology of memory.

Wirth et al.2 recorded from 145 neuronsin total, and found that 89 responded in ascene-specific manner at one or anotherphase of the session; of these, 25 changedtheir activity in close association with theanimal’s behavioural learning curve. It is thislatter subset, dubbed ‘changing cells’, thatattracted the authors’ attention. Each of the25 neurons showed robust changes in firingrate at some point following the presentationof a new scene, but little or no response to ahighly familiar scene.

Furthermore, these changing cells fell into two categories. One category consistedof neurons that showed little or no responsewhen a new background scene was presentedor during the delay period of the task. Butthey then signalled that the animal hadlearned the location of the reward-associatedtarget in that scene by significantly increasingor decreasing their firing rate. This alteredactivity was maintained throughout therecording session, suggesting that the cellswere engaged in storing memories, or inmonitoring their storage. The second cat-egory comprised neurons that responded tonew scenes by either increasing or decreasingtheir activity relative to the baseline,and thensignalled learning by returning to baseline

Neurobiology

Caught in the actYadin Dudai

Researchers may have seen the signature of a memory in the making. In monkeys that learnt to associate two stimuli, single neurons changedtheir responses before, during or after learning became evident.

When Captain Lemuel Gulliver visit-ed Balnibarbi, he was fortunateenough to be allowed into the hall

of Speculative Learning at the Academy of Lagado, where, with great admiration,he watched how the nuts and bolts of aknowledge machine generated new sentencesof great wisdom in real time1. Neurobiolo-gists can only envy him to this day. How niceit would be to watch biological learningmachines in action, and see how experienceis converted into a memory trace. In the realworld, this is more easily wished for than

done. Writing in Science, however, Wirth andcolleagues2 have moved a step closer to thisgoal. Their report is of particular interestbecause it gives fresh insight into the activityof the hippocampus — part of the brainmachinery that forms and stores declarative(consciously accessible) memories, and afocus of attention for experimenters, clini-cians and theoreticians alike3.

Wirth et al.2 trained their monkeys in aninstrumental conditioning task, in which thesubject learns, by trial-and-error, the impactof its actions on the world4. Briefly, the

© 2003 Nature Publishing Group