The Left–Right Polarity Puzzle: Determining Embryonic Handedness

W henever symmetry is broken in nature to yield only one of two equally probable outcomes, whether in physics, chemistry, or biology, there is an intriguing problem to be solved. Physicists from M. and P. Curie to T.-S. Lee and C.-D. Yang puzzled over such phenomena at the atomic level. Organic chemists puzzled over the handedness of molecules for many years after Pasteur showed that grape juice contained only one of the possible right-and left-handed mirror-image forms (enantiomers) of tartaric acid (Figure 1; see Glossary [Box 1]). And biologists continue to puzzle over the handedness of organisms. Why is there a puzzle? The embryos of most, probably all, bilaterians exhibit obvious polarities from head to toe (along the anterior–posterior axis) and back to front (along the dorsal–ventral axis), but they also exhibit less obvious left–right (L-R) differences. That is, although bilaterally symmetrical on the outside, they are L-R asymmetric on the inside. The polarity of the L-R axis determines the laterality of the body plan, for example, whether the human heart will be on the left side or on the right. There are two possible mirror-image forms of the animal body plan, just as there are for tartaric acid, differing only in L-R polarity. Almost without exception, however, the body plans of individuals in any given species develop as only one of the two possible " enantiomers. " This means that at some point during embryonic development, just as in the grape's synthesis of tartaric acid, L-R symmetry must be broken in a unique manner, so that all individuals develop with the same handedness—for example, with the heart on the left. Establishment of asymmetry in embryos is no longer a mystery; we know of several mechanisms by which a cell or a tissue can become asymmetrically polarized. The puzzle here lies in the mechanism of initial choice between two opposite polarities that should be equally probable. We now know that stereospecifi c synthesis of biomolecules like tartrate comes about because the enzymes that catalyze their synthesis are also stereospecifi c, handed molecules. As the organic chemist F. R. Japp stated in 1898: " only asymmetry can beget asymmetry " (quoted in [1]). Where does the stereospecifi c cue in embryonic handedness choice come from? Over 100 years ago, H. E. Crampton [2] observed that the handedness, or chirality, of snail shell coiling, dextral (right-handed) for some species and sinistral (left-handed) …