A common perception and belief about bilateral animals is that they are left-right (L-R) symmetric. In fact, this symmetry is often far from perfect. More surprisingly, there are reproducible handed asymmetries in bilateral animals, involving such aspects, for instance, as the dextral looping of the heart in mammals. What are the ultimate sources of handed asymmetries and what are their consequences, including behavioural ones? It was to grapple with these questions that a Ciba Foundation Symposium, ‘Biological Asymmetry and Handedness’. was held in London, from the 19th to the 22nd of February*. The meeting was organized by Dr Nigel Brown (MRC Unit. St. George’s Hospital Medical School, London), in collaboration with the Ciba Foundation, and chaired by Prof. Lewis Wolpcrt (Middlesex Hospital School of Medicine, London). The central task of the meeting, as noted by Prof. Wolpert in his opening remarks, was to explore the nature of the connections between asymmetry at the molecular level and higher order forms of handedness. As he phrased the issue: ’If, in the early history of life, D- rather than L-amino acids had been used to construct proteins, would our hearts be on the right, not the left, side of our bodies?’ The meeting began, unusually, with the immediate disproof of a hypothesis, that of the chairman (himself a lefthander), that people interested in the topic of handedncss might be disproportionately left-handers; a quick poll reviewed the percentage of left-handers in the conference to bc that of the population at large (about 10 %). The first full day of the meeting was devoted to handedness in molecules. the second day to left-right asymmetries in embryonic development, and the third, and final day. to the significance of left-right differences in brain development and construction. The progression was, in effect. from the best understood subjects to the least understood. Although the basis of molecular handedness is considerably clearer than L-R brain differences, the first talk by S. Mason (University of Cambridge) dealt with a molecular mystery, the fact that while standard inorganic syntheses of amino acids and sugars produce equal amounts of L- and D-forms (racemic mixtures). terrestrial life forms use only L-based amino acids and *The proceedings are to be published. The volume, Biological Asymmetry mid Hartdedriess (ed. J. Marsh). will bc out in Octohei-. Puhlisher: John Wiley and Sons, Ltd. Price: f3950, $69.50.

D-sugars. What were the ‘chiral force(s)’ that generated these highly asymmetric compositions? Evidence was reviewed that the electoweak force (the weak nuclear radioactive force coupled with electromagnetism) can produce a very slight chiral bias, on the order of 1 in loi7 parts. In combination with a weak selective preference for one enantiomer over another, it is possible, according to simulations by Dr K. Kondepudi (Wake Forcst University, North Carolina) that in a pond of several km diameter, over about 10 thousand years. that this very weak difference can become a preponderant one. Other talks about molecular handedness were given by J . W. Galloway (Cancer Research Campaign, L,ondon), S. Chothia (Laboratory of Molecular Biology, Cambridge), and Howard Berg (Harvard). Galloway reviewed the ubiquity of helices in macromolecules and the ways in which the handedness of monomers determine the handedness of helices. Chothia argued that above the tertiary level of folding in proteins, the handedness of monomers probably has little direct influence on higher levels of left-right asymmetry; quaternary folding patterns and interactions between different molecules (and cells) are most directly influenced by the amino acid side-chains. Berg‘s talk, dcaling with the construction of bacterial flagella and their handedness properties, provided a bridge between the purely molecular talks and those dealing with the asymmetries of single-celled organisms. Though E. cofi are single celled, they can, under the influence of certain environmental stimuli, emit signals which prompt the formation of highly symmetrical aggregates. Ciliates, cukaryotic single cells, often have distinct left-right cortical asymmetries on their ventral sides. J. Frankel (University of Iowa) reviewed various surgical experiments that can either generate symmetrical Styloniclzia or subsequently undo this symmetry, leading to cymmetry reversals. A key finding is that one can obtain global reversals of symmetry (on one side of the cell) but not isolated, localized reversals. The results can be rationalized within the framework of the polar coordinatc model, and specifically the idea that juxtapositions of positional values, over a certain range, can produce extensive polarity reversals. The second day of the conference began with an evolutionary perspective. The evolution of bilateral symmetry in multicellular organisms, particularly in deuterostomes, was addressed by R. Jcfferies (British Museum, UIC). His review of the paleontological evidence suggests that bilaterality evolved separately in thc lines leading to insects and to chordates and that, in the latter, bilaterally evolved in connection with locomotion. and the conversion of a radially symmetrical organism to a bottom-crawling one, with left-right symmetry developing from the tail anteriorly. R. Dohmen (University of Utrecht, Netherlands) reviewed the role of torsion during snail development in producing left-right asymmetry of the visceral organs and the relationships bctwccn spiral cleavage pattern (dextral v s sinistral). torsion, and shell coiling.

Cleavage pattern is under maternal genetic control and is highly determinate. Another instance of highly determinate L-R asymmetries involves another invertebrate, Caenorhnbditis elegans. W. Wood (University of Colorado. Boulder) discussed experiments in which physically shifting two cells at the 6-cell stage in C. elegans embryogenesis, can lead to complete and determinate symmetry reversals (of the gonads and intestines)('). Since many of the bilaterally symmetric features of the nematode arise from non-equivalent cleavage patterns on the left and right sides, these cell lineage patterns must be reversed as well. The data show, as does a growing body of information, that much of the fixed cell lineage relationships in the nematode embryo cannot arise from fixed 'determinants' but be a product of cell-cell interactions. These interactions must be sufficiently stereotyped to produce a highly determinate result. However, two vertebrate developmental systems, which show consistent L-R differences, show a lesser degree of determinacy, when perturbed. In Xenoyus: various treatments. at either the singlc cell (zygote) stage or much later, during the first steps of organogenesis, can produce a high percentage of animals with reversed L-R relationships (of the gut and heart), the condition of situs inversus, as described by J. Yost (University of California, Berkelcy). Thus, UV irradiation of zygotes on the ventral side, followed by rotation? can produce 25 '70 situs inversus embryos, while interference with gastrulation by injection of RGD peptides or interference with proteoglycan synthesis during migration of the cardiac primordia can produce either abolition of L-R asymmetry o r reversal of L-R symmetry(2) with frequent cases of localized reversals (in contrast to the single cell, ciliate case, discussed above). A genetically based cause of situs inversus, the situs inversus viscerum (iv) mutation of the mouse, was a topic treated in the following two talks. Mice honiozygous for this mutation show randomized L-R asymmetry(3), with localized as well as global reversals. N. Brown (MRC Unit, St. George's Hospital, London) reviewed a general model for the development of handed asymmetry(4)that can account for the randomization and discussed the effects of a-adrenergic agonists in causing randomization of asymmetry. M. Brueckner (Yale University School of Medicine) described the progress in cloning the iv gene. The gene is linked to IgH-C on mouse chromosome 12 (syntenic to human chromosome 14) and the region is being cloned and analyzed. The final day of the conference, devoted primarily to the brain and behavioral bases and consequences of L-R differences. A . Galaburda (Harvard Medical School) began with a controversial presentation to the effect that left-right brain differences cannot so far be linked to any differences in organization or neuronal connectivity patterns but only to differences in size. As determined by cell labelling experiments in the rat, these size differences arc not due to late differences in cell division rates but may reflect early differences in numbers of neuroblasts. T. J. Crow (MRC Clinical

Research Centre, Harrow) presented some data that in schizophrenics, there is an absence of certain standard asymmetric differences in size in certain brain areas, e.g. the temporal lobe. Michael Morgan (University of Edinburgh) discussed a striking instance of asymmetry in the amphibian brain, the hebencula nucleus and discussed the possibility that there is an 'ur-asymmetry' in chordates, with a preferential exaggeration of features on the left side. C. McManus (University College London) and M. Annett (University of Leicester) discussed the genetic basis of handedness in humans, which exists but is clearly complex, and compared contrasting genetic models(5"). Somewhat surprisingly in view of the evidence for a genetic element in handedness in humans, R . Collins (Jackson Laboratory) reviewed extensive evidence that one cannot select, in mice, for an increaqe in L-R bias in handedness in a population in either direction but that the strength of the response in individuals can be influenced by selection. The final talks were by J. Burns (University of Newcastle), on a genetically based isomerism condition, Ivemark syndrome, in which individuals have either two left or two right sides, and M. Peters (University of Guelph) discussed the relationship between cerebral lateralization and motor control in complex bimanual tasks. Though the neurological basis of L-R cerebral differences and L-R behavioural differences were not solved during the conference, we were left with a qtriking finding to consider. M. Corballis (University of Auckland) reported that while pigeons cannot discriminate a lower case 'b' from a lower case 'd', they can be taught to do so, if consistently blindfolded over either eye. The critical general point is that to perceive asymmetry. one must be asymmetric oneself. If pigeons can be taught to read, i t is a reasonable hope that humans will. eventually, come to understand better the intriguing developmental and neural bases of L-R behavioural difference\.

References* 1 Woou, W . U. (1991). Evidencc for rcvcrsai of handedness in C. rlegnns embryos for early cell interactions determining cell fate$. !Vaturr,349, 536-539. 2 Yosr. H. J. (1990). Inhihition of protroglycan synthesis eliminates left-right asymmetry in Xenenopus 1ae1,ircardiac looping. nevchprnent 110. 865-874. 3 L4YTON. W. M. (1976). Random determinalion of a developmental proccss: reversal of normal visceral auymmetry in tht: mouse. J . Hered. 67,336-338. 4 BROWN. N . A . AND WoLrmr, L. (1990). 'Ihe development of handedness in left,/right asymmetry. Devdoprnmt 109, 1-9. 5 MCMANUS,T. C. AND BRYDEN,M. P. (1Y91). The genetics of handedness: Cerebral dominance and lateralization. Ed. S. J . Segalowitz. Hnndbook o,f N c . u n ~ ~ ~ . ~ y ~ h voI o l o 8. g y Elsevier: Amsterdam. In press. 6 A N ~ E I M. T . ( 1 9 Y l ) . Annotation: Laterality and cerebral dominance. J . Child Psjchul. t'sychirit. 32, 219-232.

* A fuller liqting of reference? for topics discussed in the conference will be found i n the published proceedings.

Department of Zoology, University of Cambridge, Downing St., Cambridge CB2 3EJ, UK.