of this tree are dispersed almost exclusivelyby the spider monkey (Ateles paniscus ; Fig.1). Three other primate species feed uponthe tree’s seeds in the study area, but only spider monkeys ingest them intact and act as effective dispersal agents. The monkeyscan travel 1 kilometre in a few minutes andhave a gut passage time of about 4 hours. Sothe seeds can be dispersed some distancefrom the parent plant, ensuring that thegenetic structure of the population of I.ingoides is well mixed.

The research concentrated on the geneticvariability of I. ingoides populations, com-paring areas where spider monkeys were present with those where they had becomelocally extinct through bushmeat hunting.After analysing 14 enzyme systems in leafextracts, the authors found that there wasless genetic variation in the seedling popula-tions around parent trees when the monkeyswere absent than when they were present.Without the monkeys the seeds simply fall to

the ground around their parents. In otherwords, the monkeys are responsible formaintaining a thorough genetic mix in thepopulation, and in their absence a series ofgenetically more uniform patches develops.

In general, trees in the tropical rainforesthave high levels of genetic diversity. They areusually out-breeding and have efficient geneflow because of their specialized pollinationand seed-dispersal mechanisms. Fragmen-tation of the forest, whether by physicalprocesses (such as clearance) or by interrup-tion to gene flow (as in the case of vectorloss), can lead to the local accumulation ofpotentially detrimental mutations and anoverall loss of fitness. As has so often provedto be the case in ecological studies, when onelink is removed from a network, the wholesystem can start to unravel. ■

Peter D. Moore is in the Division of Life Sciences,King’s College, Franklin–Wilkins Building, 150Stamford Street, London SE1 9NN, UK.e-mail: peter.moore@kcl.ac.uk

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NATURE | VOL 409 | 15 FEBRUARY 2001 | www.nature.com 777

100 YEARS AGOSensational Newspaper Reports as toPhysiological Action of Common Salt.In the interest of the dignity of scientificresearch I venture to hope you will print thefollowing statement. Some American papershave recently published sensational andabsurd reports of physiological theories andexperiments whose authorship theyattributed to me. These reports, which inAmerica nobody takes seriously, werereprinted and discussed in European papers.I hardly need to state that I am in no wayresponsible for the journalisticidiosyncrasies of newspaper reporters andthat for the publication of my experiments orviews I choose scientific journals and not thedaily Press. Jacques LoebFrom Nature i4 February 1901.

50 YEARS AGOA recent address on “Freedom in Science”broadcast by Prof. C. A. Coulson made evenclearer the need for ensuring that ourinstruments of government make properprovision for such freedom. Prof. Coulsonobserved that, since patience, humility,tolerance, fairmindedness, integrity, co-operation and trust are the hallmarks of thescientific tradition, he has been forced to theconclusion that this tradition is ultimatelybased on, and derives its final sanction from,moral and ethical considerations which lieoutside the field of what is popularly calledscience. A. N. Whitehead maintained that theinner conviction that the world is rational, andthe confidence in one another that enables usto dispense with the verification of otherpeople’s claims, is a legacy coming to us from“the medieval insistence on the rationality ofGod”. Prof. Coulson accordingly suggeststhat in a time of crisis like the present, whichis marked by the breakdown of personalconviction among ordinary people, it is highlyimportant that… men of science are thecustodians of many of the most preciousvalues of our civilization. From this aspect,Prof. Coulson agrees with Prof. Polanyi’s viewthat the suppositions underlying our belief inscience “co-extend with the entire spiritualfoundations of man, and go to the very rootof his social existence”. But he discusses apossible danger to the freedom of sciencewhich might well arise from intoxication with power and an unmeasured faith inorganization. This will have to be guardedagainst when the Science Centre in Londonnow under consideration is established.From Nature 17 February 1951.

The sequencing of the human genomeprovides exciting possibilities to explainthe complexities of life. But some more

basic questions remain unanswered — suchas why the double-helix structure of DNAspirals in a clockwise (right-handed) direc-tion, rather than a left-handed one. On page 797 of this issue1, Ghadiri et al. use apeptide system to demonstrate how ‘homo-chirality’, or single-handedness, may haveevolved in biological molecules.

Nucleic acids, like nearly all biologicalmolecules, exhibit ‘handedness’, and onlyone of the two forms is used in a particularbiological process. This gives rise to homo-chirality, where each molecule is identical.Among sugars, ribose and deoxyribose arenot identical; nonetheless, the form of ribose in RNA and the form of deoxyribosein DNA share a common right-handed orientation of their principal functionalgroups. This common stereochemistry —the three-dimensional shape of the molecule— evokes another concept of homochiral-ity, which relates members of a family of compounds.

The natural amino acids share a commonstereochemistry, as they are all left-handed(L-amino acids). This raises the question of whether homochirality within a family of biological molecules is the result of a stereochemical cooperativity (diastero-

selectivity) among the members within abiopolymer. Indeed, our enzymes and nucleic acids are composed of predominantlyL-amino acids and D-sugars — we are unableto use the opposite-handed bioploymers.Why not? Attempts to answer this questionby mimicking the creation of a homochiralenvironment in the laboratory have beenunsuccessful until now.

This difference in functional chiral formhad tragic consequences in the 1960s whenpregnant women were given a sedative(Thalidomide) that was a mixture of theright- and left-handed forms of the drug; one of the two forms, or enantiomers, gaverise to birth defects. That two enantiomerscan have such different functions shows that stereochemistry controls whether, andhow, molecules recognize one another and‘shake hands’.

The origin of one-handedness in bio-logical molecules is not yet clear2. Severalexplanations have been put forward toexplain how homochirality came about, butall are speculative — it is not even known yet whether it arose by chance or by someother means3,4.

Synthetic polymers are simpler than bio-logical systems and provide a model forunderstanding the origin of homochirality in biomolecules. One proposal stems fromobservations that polymers made from

Biochemistry

Single-handed cooperationJay S. Siegel

Our bodies use only ‘left-handed’ amino acids and ‘right-handed’ sugars.Hints are now emerging on how this handedness evolved and howcooperativity among like-handed molecular components came about.

© 2001 Macmillan Magazines Ltd

building blocks of random handedness willcontain mixtures of right- and left-handedblocks so complex that no two polymers will have identical stereochemistry. All thepolymers will be chiral, but if one exists, it is unlikely that its mirror image will too5. For small polymers consisting of only a few building blocks, the number of possiblecombinations of right- and left-handedblocks is small, and the mirror images areeasily formed. However, for a polymer com-prising 20 building blocks there are almost a million possibilities, and an enormous number of blocks would be required to buildall the possible mirror images. Biologicalmolecules often have over 100 buildingblocks, pushing the limits of available mat-erials and making it extremely unlikely that a molecule and its mirror image can be prepared in the same batch. If the sample of polymers contained some that were self-replicating, it is reasonable that the most efficient one will emerge, and only thishomochiral polymer will exist6.

In complex organisms and living systems,

homochirality manifests itself in families of related biological molecules, such as the naturally occurring L-amino acids in a pro-tein. The presumption here is that there iscooperativity among these biomolecules intheir biopolymers or underlying structure.The polymer example above alludes to anoptimum self-replicating polymer. Can weform a general rule that homochirality leadsto optimal function? With regard to self-replication, this question can be addressedby stereochemical analysis and reactionengineering. However, engineering the para-meters of biochemical processes to obtainappropriate stereoselectivity — choosing of the preferred mirror image — has notbeen trivial. Poor reaction selectivity andinhibition of replication have plaguedresearchers who would like to mimic lifethrough protobiology7.

Ghadiri et al.1 find a stereoselective reaction, between two chiral peptides, thatuses the product of their coupling to replicate— a process known as ‘autocatalysis’. Theirresults indicate that this self-replicating

system could perpetuate homochirality,because a left-handed template is competentto bring together only those fragments thatare also left-handed. The authors also showthat, even if only one out of 15 buildingblocks has opposite handedness, autocataly-sis is significantly diminished. Such a resultestablishes that homochiral peptides aremost efficient at autocatalysis.

The authors also found that even thougha single ‘mutation’ with regard to handed-ness could hamper autocatalysis, the samemutant template was reasonably effective at catalysing the combination of two pureleft-handed fragments. The combination ofthese results supports the idea that a poly-mer evolution experiment would ultimatelyresult in homochirality of biological molec-ules. Furthermore, these results support ageneral principle that similarity in buildingblocks leads to higher-order structure, likethe spiral shape of a ram’s horn or a crystal-lattice structure8.9.

Given the fundamental nature and per-vasive occurrence of chirality in biologicaland non-biological macromolecules, it isreasonable to postulate that homochiralityexisted long before the genetic informationof life was encoded. Once in place, this sense of chirality perpetuated throughoutearly life systems and has become a part of complex biochemical processes such astranslation and transcription. So the linearsequence of information on the genome ispassed along owing to the three-dimensionalstructure of the DNA double helix, and must now include the coding for homo-chirality that we see in amino acids. We nowhave a model system that may bring us closerto understanding why we see cooperativityamong homochiral biological moleculestoday. ■

Jay S. Siegel is in the Department of Chemistry,University of California San Diego, La Jolla,California 92093-0358, USA.e-mail: jssiegel@ucsd.edu 1. Saghatelian, A., Yokobayashi, Y., Soltani, K. & Ghadiri, M. R.

Nature 409, 797–801 (2001).

2. Bonner, W. A. Orig. Life Evol. Biosph. 25, 175–190 (1995).

3. Siegel, J. S. Chirality 10, 24–27 (1998).

4. Berger, R., Quack, M. & Tschumper, G. S. Helv. Chim. Acta 83,

1919–1950 (2000).

5. Green, M. M. & Garetz, B. A. Tetrahedr. Lett. 25, 2831–2834

(1984).

6. Bolli, M., Micura, R. & Eschenmoser, A. Chem. Biol. 4, 309–320

(1997).

7. Kozlov, I. A., Politis, P. K., Pitsch, S., Herdewijn, P. & Orgel,

L. E. J. Am. Chem. Soc. 121, 1108–1109 (1999).

8. Kuhn, H. & Waser, J. Angew. Chem. Int. Ed. Engl. 20, 500–520

(1981).

9. Thompson, D. On Growth and Form 346 (Cambridge Univ.

Press, 1961).

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Daedalus

David JonesDavid Jones, author of the Daedaluscolumn, is indisposed.

Bone is a dynamic structure,constantly being formed (bycells called osteoblasts) andresorbed (by osteoclasts). Theactivities of these cells must befinely balanced. If resorptionexceeds formation, the result is the weakened, brittle bonescharacteristic of osteoporosis. In osteopetrosis, by contrast, not enough bone is resorbed:the osteoclasts malfunction,leading to dense yet fragilebones with no bone marrow.Writing in Cell (104, 205–215;2001), Uwe Kornak, DagmarKasper and colleagues identify amolecule that is needed for thebone-resorbing cells to function.Their results may explain somecases of an inherited disease,infantile malignantosteopetrosis.

During bone resorption,osteoclasts attach to the bonematrix and form a specializedouter membrane, called theruffled border, facing the bone.Bone-digesting enzymes arethen transported out of the cell,across this border. The enzymesneed an acidic environment tofunction, so the osteoclasts alsopump out protons. At the sametime, chloride ions are let out of

the cell to maintain the electrical balance. The protein-based channel thatselectively allows the efflux of chloride ions has beenelusive, but the authors suggestthat it is a molecule called ClC-7.

Kornak et al. engineeredmice with a disruption in thegene encoding ClC-7.Theresulting mutant mice (one ofwhich is pictured above, with anormal mouse) had all thecharacteristics of osteopetrosis,including short limbs andabnormally dense bones. Themice also failed to form bonemarrow, as can be seen bycomparing the two high-magnification X-ray imagesabove. Moreover, osteoclastsisolated from the mutant micewere unable to absorb bone.

The authors tracked down the ClC-7 protein to the outer membrane andcertain acidic organelles, called lysosomes, in theosteoclasts of normal mice. But there was no ClC-7 proteinin these cells in the mutantmice. Although the osteoclastsfrom the mutant micecontained the usual protonpump in their outermembranes, they were unableto acidify the extracellularspace — presumably becauseof the defect in ClC-7. Finally,Kornak et al. discovered that a patient with infantile malignant osteopetrosis has a disrupted ClC-7 gene. All inall, they make a convincingcase that this chloride channel is crucial for boneresorption. Amanda Tromans

Medicine

Channel fault in osteopetrosisNormal

Mutant

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