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CHAPTER 6 OPTICAL ASYMMETRY LUBERT STRYER What significance would we attribute to a finding of net optical activity on Mars? Suppose that several dozen samples taken from different parts of the planet were consistently to show a thousandfold preponderance of the right-handed form of a particular chemical species. A consideration of the possible sources of net optical asymmetry leads to the conclusion that such an observation would in itself be a strong criterion of life on Mars. The invariant association of net optical activity and terrestrial life was first noted by Pasteur, "Artificial products have no molecular dissymmetry ... I could not point out the existence of any more profound distinction between the products formed under the influence of life, and all others." [Pasteur, I860]. A century of biochemistry has demonstrated that this distinction between L and D isomers is nearly always observed in biochemical processes. Sometimes, both enantiomers are utilized, but in that event they appear in different structures. The enzymes of bacteria contain only the L-amino acids, while both isomers are found in the cell walls. With glucose, only the D-form is found in nature. The molecular basis of this selectivity resides in the fact that the mirror image forms lose their equivalence upon interacting with a second optically active molecule; the resulting diastereoisomers in general have different properties. The relationship of optical activity to the origin of life has been discussed by numerous authors [Wald, 1957; Fox et al., 1956; Horowitz and Miller, 1962; Oparin, 1957; Ulbricht, 1962; Wheland, 1953]. 141

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142 RECOGNITION OF LIFE AND SOME TERRESTRIAL PRECEDENTS It is not merely our earth-bound experience that gives stress to optical activity as a criterion of life. We infer its significance from a more general consideration of the entropy of living systems. In a system in which left is equivalent to right, the existence of optical activity can be due only to fluctuations. We are, of course, interested in detecting the most extreme fluctuation from thermodynamic equilibrium, life itself. A search for optical activity is thus a direct attempt to establish the existence of one of the most general characteristics of life processes, their fluctuations, without any prior notion about the type of chemistry utilized by that particular form of life. Can there be net optical activity without life? A thorough consideration of this question is indispensable in deciding the priority and emphasis to be given to optical activity in a search for extraterrestrial life. Three hypothe- ses for the acquisition of net dissymmetry have been cited in the litera- ture. The first of these involves the use of circularly polarized light to effect a photochemical change [Kuhn and Braun 1929]. Net optical activity may arise through the preferential decomposition or synthesis of one of the enantiomers, as has been experimentally demonstrated. A second pos- sibility is the dissymmetric action of an optically active catalyst, such as an L-crystal of quartz. For example, a racemic mixture of 2-butanol was selectively dehydrated at high temperature on a catalyst consisting of a metal deposited on a quartz crystal [Schwab et at., 1934]. A third mechanism, the spontaneous development of dissymmetry from optically inactive starting materials without the apparent participation of dissym- metric substances or forces has been reported. For instance, a solution of methylethylallylphenyl ammonium iodide in a test tube was found to have optically active crystals and an optically inactive mother liquor after the lapse of a few months [Havinga, 1954]. It must be stressed that each of these hypotheses can, at most, lead only to local dissymmetry, and not to the acquisition of net optical activity of the same handedness in many samples taken from sites geographically far apart. A fortuitous excess of left circularly polarized light may produce an excess of, say, the L-isomer. But it is equally likely that at some other site, an excess of right circularly polarized light shines, and in that environment the D-isomer will correspondingly predominate. The same considerations apply to optically active catalysts such as quartz. Here and there we may find an excess of one of the crystalline forms. But the preponderance is only local. Moreover, these fluctuations will tend to disappear with the passage of time. Optical purity is bound to deteriorate, since the free energy of racemization is negative. Kuhn has derived an expression for the persistence time of optical purity that is produced by means of an optically active

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Optical Asymmetry 143 catalyst from inactive starting material [Kuhn, 1958]. Take a first-order reaction with a AF° of 3 kcal/mole, in which the synthesis occurs in 10 minutes, and where the products are 99.95 per cent L- and 0.05 per cent D-isomer. After 3 months, the concentration of the D-antipode will have increased to five percent. In time, the concentration of the D- will ap- proach that of the L-antipode unless the reaction products are removed from the catalyst, either spatially or by subsequent chemical reactions. This is, of course, the manner in which a high degree of optical purity is assured in biological organisms. In the absence of life, such a unidirectional flow of optically active species is less likely. Thus the long-term persistence of optical activity generated via fluctuations is improbable in systems which are allowed to approach thermodynamic equilibrium. For this reason, greater significance should be attributed to a rinding of net optical activity in atmospheric samples in contrast to samples derived from solid material that has had less opportunity to attain thermodynamic equilibrium. In this discussion, the equivalence of left and right has been implicit. However, the non-conservation of parity vitiates this assumption, at least for weak interactions. Thus, when /3-decay occurs, as in 60Co—»60Ni + e- -f- v, the emerging electrons have excess left circular polarization [Gold- haber et al., 1957]. This has raised the question whether there is a link between this dissymmetry of fundamental particles and the structural dissymmetry of molecules [Ulbricht, 1959]. Is it possible that optical activity arises through the action of the excess left circularly polarized electrons produced in all /3-decays? The few experimental attempts to carry out asymmetric syntheses with circularly polarized electrons have yielded negative results [Ulbricht, 1959]. Unless it is shown that this intrinsic dissymmetry at the level of weak interactions can be imprinted on covalent chemistry, we are justified in retaining the notion that left and right are equivalent at our level of concern. In summary, we conclude that net optical activity in the absence of life is highly improbable, and so a positive finding of net optical activity, defined previously, would be highly suggestive of the existence of life. In contrast, a negative finding would be more difficult to interpret. It is conceivable that net optical activity might go undetected, due either to inadequacies of the sampling and fractionation procedures, or to limitations of instrumental sensitivity. These potential difficulties are not intrinsic to the use of optical activity as a criterion of the existence of life. Rather, they are imperfections that reflect the present state of experimental methods, and which can, and in fact must, be overcome in an appropriate develop- ment program for extraterrestrial explorations. Let us assume that a finding of the absence of net optical activity can be taken with confidence at its full face value. The more subtle question then

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144 RECOGNITION OF LIFE AND SOME TERRESTRIAL PRECEDENTS arises, namely, can there be life without optical activity? Our terrestrial experience strongly argues against this conjecture. Life as we know it rests on a high degree of steric selectivity. A biochemistry of racemic mixtures is entirely inconsistent with steric selectivity, since the distinction between an L- and a D-antipode in its interaction with an optically active molecule is so gross that it cannot be ignored. Alternatively, an absence of net optical activity might be due to a total lack of optical stereoisomerism, per se, rather than to the cancelling of optical activity by equal amounts of the antipodes. However, a biochemistry of this sort would, at best, be a primi- tive one. Obviously, a severe restriction would be placed on a carbon-based biochemistry that would be forced to exclude compounds with asymmetric centers or other sources of dissymmetry. These considerations, which argue against the likelihood of life without optical activity, are suggestive but not compelling. We do not know enough about the evolution of terrestrial life to rule out the possibility that a primitive stage of racemic life once existed here. In fact, we are quite uncertain whether net optical activity preceded the onset of life on Earth, or closely paralleled its emergence, or was the consequence of natural selection by established, though primitive, organisms. In summary, we conclude that the absence of net optical activity virtually precludes the possibility of life possessing a degree of complexity akin to ours. The existence of primitive forms of life without optical activity is a matter of conjecture, but the possibility cannot be excluded on the basis of optical rotatory measurements. At present, optical activity is a relatively insensitive measure of the predominance of one of the antipodes of a particular molecular species. Under the most favorable conditions, as little as 1 ^g could be detected, as for example hexahelicene [Moscowitz, 1961] and d-urobilin [Gray et al., 1959]. In general, the sensitivity is considerably less. Since the informa- tion gained from rotatory measurements can be highly significant, it is im- portant that the method be developed as fully as possible. Two approaches should be pursued: (a) enhancing the physical sensitivity of the detecting apparatus; (b) enhancing the magnitude of the rotation itself through chemical means. We shall consider the second of these in the discussion which follows. It is well known that the molar rotation of an optically active species can be increased through the formation of an appropriate derivative. Such a derivative may be either a covalent compound or a molecular complex [Lowry, 1935]. For example, the molar rotation of L-proline at 589 m/j. is about —100°, while that of the dinitrophenyl derivative is nearly —2000°. A 20-fold enhancement of this kind is by no means unusual. However, at

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Optical Asymmetry 145 best, it will allow for the detection of not less than 1 /tg of the optically active species. If the sensitivity is to be enhanced by several orders of magnitude, then it is evident that the optically active molecule must act as a stereo-specific catalyst for a readily detectable process. For instance, the optically inactive dye pseudoisocyanine polymerizes under certain conditions to form high molecular weight helical micelles [Rich and Kasha, 1964]. Ordinarily, an equal number of right and left handed pseudoisocyanine helices are found. However, an optically active molecule may form a complex with pseudoisocyanine, and consequently one of the pseudoisocyanine helices may become favored. In fact, this has been observed in the case of the helical poly-L-glutamic acid: pseudoisocyanine complexes [Stryer and Blout, 1961]. A virtually catalytic amount of poly-L-glutamic acid leads to a gross excess of one of the screw-senses of the pseudoisocyanine helix, which has an exceptionally large optical rotatory power. In general, we can expect that a single optically active molecule will induce optical activity out of proportion to its molar concentration in a large number of molecules that were previously inactive or racemic. Another chemical amplification of optical stereoisomerism is achieved when a supersaturated solution of a racemic mixture is seeded with a microcrystal of one of the antipodes. Preferential crystallization of that antipode has been shown to occur, thus leaving a solution that is optically active on account of the relative excess of the other antipode remaining in solution [Harada and Fox, 1962; Greenstein, 1954]. If an optically active compound can serve to initiate a covalent polymeri- zation, an additional chemical amplification technique may prove feasible. The structure of the polymer may, in part, depend upon the stereochemistry of the initiator. For example, the conformation of poly-y-benzyl-L-gluta- mate has been shown to be dependent to a certain extent upon whether the initiator is a short chain L- or D-glutamate peptide; for the L-initiator, a right handed o-helix is produced, while for the D-initiator, it is left handed [Doty and Lundberg, 1956]. In this particular case, the influence of the initiator persists over relatively few residues. In principle, however, the effect might extend over hundreds of residues if the free energies of the alternative structures that are produced by polymerization in the absence of an optically active influence do not differ too greatly. Finally, we note that optical activity is merely one of a number of ex- pressions of an excess of left or right handedness, which is the phenomenon of fundamental interest to us. Other physical manifestations of a preferred molecular screw-sense, such as circularly polarized scattering, fluorescence and dichroism, may prove to be more sensitive and should be explored.

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146 RECOGNITION OF LIFE AND SOME TERRESTRIAL PRECEDENTS REFERENCES Doty, P. and Lundberg, R. D. (1956), Configurational and Stereochemical Effects in the Amine-initiated Polymerization of N-carboxyanhydrides. 7. Am. Chem. Soc. 78, 4810. Fox, S. W., Johnson, J. E., and Vegotsky, A. (1956), On Biochemical Origins and Optical Activity. Science 124, 923. Goldhaber, M., Grodzins, L., and Sunyar, A. W. (1957), Evidence for Circular Polarization of Bremsstrahlung Produced by /3-rays. Phys. Rev. 106, 826. Gray, C. H., Jones, P. W., Klyne, W., and Nicholson, D. C. (1959), Nature 184, 41. Greenstein, J. P. (1954), Advances in Protein Chem. 9, 129. Harada, K. and Fox, S. W. (1962), A Total Resolution of Aspartic Acid Copper Complex by Inoculation. Nature 194, 768. Havinga, E. (1954), Spontaneous Formation of Optically Active Substances. Biochim. Biophys. Acta 13, 171. Horowitz, N. H. and Miller, S. L. (1962), Current Theories on the Origin of Life. Fortschr. Chem. Org. Naturst. 20, 423. Kuhn, W. and Braun, E. (1929), Photochemische Erzeugung Optischaktiver Stoffe. Naturwiss. 17, 227. Kuhn, W. (1958), Possible Relation Between Optical Activity and Aging. Adv. Enzymol. 20, 1. Lowry, T. M. (1935), Optical Rotatory Power, Longmans. Green and Co., Ltd., London. Moscowitz, A. (1961), Some Applications of the Kronig-Kramers Theorem to Optical Activity. Tetrahedron 13, 48. Oparin, A. I. (1957), The Origin of Life on the Earth, pp. 189-196, 3rd Edition, Oliver and Boyd, London. Pasteur, L. (1860), Researches on Molecular Asymmetry, 46 pp. Alembic Club reprint #14, E. and S. Livingstone, Edinburgh. Rich, A. and Kasha, M. (1964), Personal communication. Schwab, G. M., Rust, F., and Rudolph, L. (1934), Kolloid-Z. 68, 157. Stryer, L. and Blout, E. R. (1961), Optical Rotatory Dispersion of Dyes Bound to Macromolecules. Cationic Dyes: Polyglutamic Acid Complexes. J. Am. Chem. Soc. 83, 1411. Ulbricht, T. L. V. (1959), Asymmetry: The Non-Conservation of Parity and Optical Activity. Quart. Revs. 13, 48. Ulbricht, T. L. V. (1962), The Optical Asymmetry of Metabolites. In: M. Florkin and H. S. Mason, eds., Comparative Biochemistry, 4, Part B, pp. 1-25. Academic Press, New York. Wald, G. (1957), The Origin of Optical Activity. Ann. N. Y. Acad. Sci. 69, 352. Wheland, G. W. (1953), Advanced Organic Chemistry, pp. 230-250, 2nd Edi- tion, Wiley and Sons, New York.