Stereochemistry and the Origins of Life James H. Brewster Purdue University, West Lafayette, IN 47907 What is life? When and where and how did it begin? For the open, questing, and critical mind there can he no final answers. Not from philosophy and not from religion. Not even from science, although it offers us an increasingly clear and detailed picture of how life has developed since about 3.4 X lo9 years ago (I), when single-celled entities appear to have existed in what is now Swaziland. Since the oldest surviving rocks (-3.8 X 109 years old (2)) are not much more ancient, geology may not he able to take us hack t o the very heginnings of life. But the earth itself is about 4.6 X 109years old (2) so that, allowing time for i t to cool from a molten state, there may be onlfa few hundred million years of life's existence unaccounted for. For that period of time, the best that science can do is to offer us mork and more sobhisticated chemical scenarios for how life might have begun, based on familiar principles that can he demonstrated in the lahoratory' (4-8). The ultimate test of these scenarios will he their ahilitv to sureest wavs to create nrimitive life forms de nouo in the laboratory. T o do so would provenothing historically hut it would serve to demystify the subject of the origin of life and that is a legitimate goal of science.2 That much demvstification remains to he done is shown by by a recent "~rovicativeOpinion" in THISJOURNAL Gonzalez (9). He asserts that the monochiralitv of living organisms, known since the heginnings of ~r~anicstereoche: mistry (10, l l ) , cannot he accounted for by modern concepts in that field and appears to contravene-the second la; of thermodynamics. This, he claims, casts doubt on the Theory of Evolution and, further, suggests that the prehiotic hands of some Great Resolver must have been involved a t some point in the origin of life. Those assertions are wrong; the suggested supernatural intervention-which, of course, can
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This is an area with a rich and joyful literature, characterized by iivelv land sometimes extravanant). soecuiation. . . inoenious land . often carei"l)experimentation, and enthusiastk (if occas onaliy premature) pubiicat on. of wnicn the sobersioes chemist may be unaware. For the ialest segment of a running annual bioliography (entries 5287-5566) see ref 3. TO demystify is not to triviaiize. Students of paleontology or molecular bioloav -. often end uo more in awe of the oiories and intricac es of life than have, eg:, those men of God whchave been capaole of burning witches and senang young men into oanle, to kill and die over dfterences in religious doctrme. Chirality is only one of the attributes shared by modern forms of iife. Others include: encapsulation of protoplasm by cell membranes, a nucieic acid-protein economy, a common genetic code, a common set of structural building biocksand metabolites,andreiated enzymatic processes. Taken together, these attributes suggest a common ancestry, but it is not required that any of them have been possessed by the most primitive iife forms. We should not mistake the last common ancestor (LCA) for the first living enfify (FLE). Studies of homologies in nucieic acids and proteins appear to be able, thanks to the conservative powers of natural selection, to allow the development of a detailed famiiv tree back to the LCA and even to orovide Some DiCture of it (see. for examole. sense t h. e ,~~.refs 12 -. 13 ~. 1 4,. In this.. . LCA is an historcal eniity w h m isaccessible to sclent:f~c study. But it may well have oeen hundreds of millions of years more recent than the FLE; it may well have had many contemporaries, some reiatedand some not, whose lines have died out leaving no trace in the genes of modern living beings. The FLE, on the other hand. has ieft no certain tracks. If iifeformed easily. early, and often,as some havesuggested, the FLEmay not even have been ancestral to the LCA. if it was silicate-based (8),there may have been no organic trace to be ieft.
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never he categorically ruled o u t i s not required to account for the monochiralitv of life. The matter deserves extended discussion because, as Gonzalez properly points out, there are important gaps - . in even the most carefullv elaborated srenarios and hecause some of the chemical speculation in this area seem.; to l w misdirected. Hut it is much too soon to say that science has struck out on this matter. Science has not exhausted thr resources of its intellectual machinery, which has an innate capacity for self-correction and redirection. For only a little more than 40 years has it seriously nddressed the hv~othesisthat life had a natural land essentially chemical? brigin. A great deal of progress has been made in that time and work on that hypothesis has made important contributions t o our understanding of contemporary life processes; we can expect further progress. Give science a chance-after all, philosophy and religion have had thousands of years to work on their answers! The observable fact is that, with some highly specific exceptions, the principal and characteristic organic compounds of the terrestrial biota are not only chiral hut (within limits of detection) almost always enantiomerically pure in their individual occurrences and of the same chiral sense in the various species.3 T o an organic chemist familiar with difficult resolutions, easy racemizations, and low optical yields, this is a t first an astonishing state of affairs (4,5, l l ) , and it has o r o m ~ t e dsearches for nhvsical nhenomena that might h a ~ ~ p r o d k ae pool d of chirh Eompounds from which the first living entitv (FLE) mieht form (15.16). . . . But there iinoth&extraordTnary about organic reactions that give mixtures of products in ~ r o ~ o r t i o remote ns from whatihey would he a~equllihrium.~ h processej h are said to hesubiect to kinetic, rather than thermodwamic. ~ r o d u c t control 67).I t is only required that the factors co&olling the relative free energies of the transition states he different from those con troll in^ the relative free energies of the products and that the products not he brought into equilibrium. Thus, it is possihle to convert an a,@-unsaturated ketone (more stable) to the @, y isomer (less stahle) via kinetically controlled protonation of the enolate (18) . lea . .1). , Selective catalysts faior one transition state more than another, sometimes facilitating formation of the less-stable stereoisomer. as in the hydrogenation of disuhstituted acetylenes t o cis: olefins (19) (eq 2). V ~ Nhigh degrees of kineticallv controlled asymmeiric synthesis-havebeen achieved in certain hydrogenations with chiral Wilkinson-tvpe (homogeneous) ~ ~(eq 3). c&aly&, as in the course of a synthesis d f b d (25) Clearly, then, the spontaneous formation of a system having a significant enantiomeric imbalance would he possihle if the chiral product were, itself, an efficient, stereospecific catalyst for the process. The very first such entity formed will replicate itself rapidly; if the starting system is achiral, or racemic hut labile, the entire sample could go over to one enantiomer. Examples of such spontaneous resolution (21) are important because they show that such processes are, indeed, thermodynamically feasible.
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Darwin's "warm little oool" (25) all to itself. Probablv consisting of only a few mhecul& and therefore nonstat&ical, probably complex enoughto be chiral, i t would, by autocatalytic, stereoselective, kinetically controlled self-replication, brine- chiralitv to a waitine- and essentiallv racemic world. There is an alternative scenario that turns out, in the end, to be much the same. Imagine a world populated with the progeny of a large number of independently formed, selfreplicatine entities. This mieht well be a racemic. if isotac" tic5, world. But now imagine a major mutation-as closure of the protein-nucleic acid re~roductivehvoercvcle ". " (7). . . Such an event might be unique and might involve a single molecule, or, more likelv, a set of stereochemicallv linked molecules. If i t conferred an overwhelming reproductive advantage i t would result in global conquest by the new species and extinction for the r e s t l ~ uthat t siecieskould consist of only one enantiomer because its ancestral molecule(s) would be the only one(*) to have desrendanrs in the new regime. Thus, chirality might also have originated quite late in the game. We would aeree with (;nnealez (9) that there is no need to " invoke the prebiotic formation of a pool of chiral intermediates-via photochemical synthesis or degradation with circular-polarized light (29-31), nonconsewation of parity in certain nuclear processes (32.33) or the weak nuclear current (34,35P, adsorption on chiral crystals (30.37) or even on achiral crystals (38), or via assorted other astronomical (39), physical, or mechanical forces (40). Kinetic bistability (23, 24, 41-43), as above or as in spontaneous resolutions, will do, early or late. But even this is not the whole answer. Would not an active, recycling system such as the terrestrial biosphere tend to approach a state of thermal equilibrium (including chiral eauivalencel of reactants and-oroducts under the principllof microscopic reversibility? indeed i t would, if the svstem were closed. But it is not: it receives a steadv innut of energy from the sun and the ;ore of the earth. it is only required that this energy be used by the biota (as a whole) to drive its lifecycles and autocatalytic hypercycles (7) to pro-
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Consider the well-studied case of l,lf-binaphthyl (22) (eq 4).
The enantiomeric forms of this substance are readily interconverted via rotation about the central bond in the fluid (melt or solution) state. less easilv so in the solid. There are two crystal forms: a racemate (containing paired enantiomers). melting a t 145 OC. and a conelomerate (with individual crystals of the R and S forms? melting at 158 "C. If, between those two meltina points. a melt is seeded with a crystnl of one enantiomer;a.moreor less romplere conversion of the entire sample to that form occurs. In a statisrical study, ofsome 200runs insealed tubes, it w a s s h o w that the vacemic) melt, induced lo crystallize by a brief touch with a piece of Dry Icr, gave degrees uf spontaneous re9olution ranging from almost none to nearly complete, with equal urot~ahilit\'for the two enantiomers. It seems likelv that the highest degree of resolution occurred when the smallest number of seed crystals was formed. One would expect that, if only one seed crystal were formed, then complete resolution would result. Going further, it was found that the solid racemate is more stable below 76 "C but less stable above that temperature. Accordinglv. a racemic sample-which. as Mills (23) has pointed ou< will statisticall; have a slight excess of one or the other enantiomer-would exist below 76 'C as racemate crystals with a few crystals of the excess enantiomer, optically pure. When the sample is heated above 76 OC, these latter crystals would seed a conversion of some of the racemate to the chiral form. I t was found that a racemic sample in a sealed tube can, in fact, undergo spontaneous resolution simply, on alternate heating and cooling above and below 76 "C. The success of a spontaneous resolution depends on several specific circumstances. The oroduct must cwstallize as a con&omerate so that chiral crystals can be removed from the zone of reaction; the reactant must be achiral or easv to racemize; the foimation of seed crystals must be d i f f i h t enough that statistics favor chiral imbalance-thus. if onlv one seed crystal forms i t will be monochiral4 and thd resolu~ tion will be complete. Gonzalez (9) certainly is correct in arguing that the spontaneous resolution of key precursors to life is too improbable to be taken seriously as a cause of biochirality. On the other hand, i t is equally certain, as Mills (23) and Wald (24) point out, that, if spontaneous generation of life is difficult, then the first living entity would have had ~
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'The probability that a coin will fall "heads" in one toss is 0.5, but the probability that it will fall with some face uppermost is 1.0. An isotactic polymer is one in which successive asymmetric centers have the same configuration. This orderly structure allows formation of helices and sheet-like structures. stabilized bv, close oackina" and bv, hvdroaen bondina. aossible. in tvoical -. when that is - ~ - -- -. as -. .,r . b opolymers. lsotactic polymers have hgher melting pomts, lower so ~bilitiesand greater reslsrance to hydrolysis (26). n a primora al world where polymers were being alternately formed (e.g., on lava surfaces)and hydrolyzed, isotactic polymers would survive and be available as regular crystal-like surfaces on which templated growth-the first form of self-replication-could occur. Once selfreplication occurs, Darwinian evolution enters as a major directing a-~ force. and selection for isotacticitv would occur. The fact that ~-~~ nonenzvmatic temolated aliaanucleotide svntheris ,~ . , .is terminated when the wrong enantiomer enters a chain (27) indicates only that irreversible polymerization of racemic nucleotides is an unlikely source of long isotactic chains. It lends support to the notion that. since prebiotic synthesis of large amounts of nucleotides is unlikely (2@,they may not have been involved in the very earliest stages of life (8).At the isotactic. and possibly proteinaceous, stage, life may well have been essentially racemic, just as a synthetic isotactic polymer is. B T h ~Mason ~ . (36)has suggested that the chirality of the electron would lead, for an a-helix or &sheet peptide, to an enantiomeric excess of 106 L molecules per mole of racemate. But Mills' formula (23) indicates that, on average, a mole of "racemate" would have a chiral excessof about 5 X 10" molecules.On this basis, it would take a contiguous sampleof about 3 X 10" molesof material for the weak neutral current effect to equal that due, on average, to chance alone. Not impossible perhaps, on a global scale, but certainly requiring a rather large "warm pond.
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duce a "dissipative system" in steady, or even increasing, disequilibrium (44). Such a system, fueled by photosynthesis (45) and using efficient metabolic cycles, could maintain a high level of high energy components (as earth, with its biosphere and oxygen atmosphere, does). I t could maintain a state of chirality imbalance. I t could evolve ever more diverse and intricate organisms. None of these results would violate the second law of thermodynamics because that law applies only to closed systems. We may call on organic stereochemistry again for a simple, reproducible example of such a svstem-the ~hotostationarvstate obtained by irradiating itilbene, in ahich the less stable cis isomer Eonstitutes 68% and the more stable trans isomer 32% (46).
Of course this argument holds, under the Theory of Evolution, only if the retention of chirality would confer a biologiof individuals, or even cal advantage on individuals, the whole biota.7 We would suggest that the fact of retention does, of itself, suggest that racemization would do no good or even be disadvantageous (47, 27).5 This is not an utterly circular argument. Living svstems can and do. in special " cases, prepare the other enantiomer or a more or less racemic mixture. Thus.. d.. 1 and dl-lactic acid can be obtained from various biological sources; d-carvone is present in caraway seed oil and 1- in oil of spearmint; (optically impure) d-apinene is found in North American turpentines and 1- in Eurooean (48): D-amino acids are found in a number of antib:lotics and in special peptides whose function requires resistance to digestion (49). Some enzymes go both ways (50), as dehydrogenases containing nicotinakide (51a,b) and S-keto acid decarboxylases, one of which apparently gives net racemization ( 5 1 ~ )This . being so, it might be expected that living organisms would long since have laid down the entropic burden that chirality entails were it advantageous to do so-just as cave-dwelling fish have evolved to eliminate their eves. The chiral way of life offers many advantages, especially to the more highly organized (and more recently evolved) forms of life-notably in the synthesis of special products, the development of metabolic cycles, and the construction of biopolymers. Specialty products produced in small amounts, as vitamins, hormones, pigments, flavorants, defensive materials, or even metabolic waste do not always contain chiral centers, but if they do, their chirality reflects the efficiency to be gained by using one set of enzymes instead of two. The use of proteins as catalysts may well be as ancient as life itself; i t is, a t any rate, a habit the terrestrial biota would find hard to give up. Since any individual protein molecule, even if not isotactic, must be chiral? i t will, in principle, be more effective as a catalyst when the individual molecules i t processes and oroduces are of one chiralitv rather than the other. A c k a l catalyst forms diastereomeric transition states with enantiomeric substrates. I t is a cardinal principle
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'The Theory of Evolution is onen interpreted in a "dog-eatdog" manner to suggest that only those traits that benefit individuals would promote survival. The development of social insects and mammafs with herd instincts indicates otherwise. Beyond that, it seems clear that traits that confer temporary advantages on individuais or groups-but might promote destruction of those parts of the environment that serve for life support-may have a negative survival value in the long run and even lead to extinction of the species. Let mankind
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Thus, a dipeptide containing one D- and one L-unit of the same amino acid is not meso; the individual molecules are chiral.
of organic stereochemistry that diastereomers (unlike enantiomers) differ in chemical and physical properties. The more efficient a chiral enzyme is, the more likely i t is to be highly stereoselective. On this basis, a proteinaceous life form could produce a racemic product only if it used a nonselective and therefore inefficient enzyme, a pair of enzymes (one for each enantiomer) or a racemase; i t could produce an optically pure product with a single enzyme of high efficiencv. On balance. evolutionarv pressures would be expected to in fiver the simpler system. This effect would be the middle and late erasof the development of life, where the specialty products would be expected to evolve. The same advantage accrues in the development of metabolic cycles, which aie important means of maintaining the degree of disequilibrium that is required for life to endure. There will he an additional advantage if the pool of intermediates is already stereochemically homogeneous so that there is no need for a mechanism for screening out enantiomeric reactants that might act like sand in the gears. This biological advantage of chirality would develop early on as a basic feature of life and would play an important role in conserving chiralitv later on. Perhaps most i m ~ o r t a n t life , as we know it is constructed of i s o t i t i c biopol&ers, in which the building blocks are all of the same chirality. This has the advantages we have already seen in requiring not two, but one scheme for the synthesis of intermediates and in ensuring that those intermediates will he enantiomerically correct. (Compare the efficiency of an assembly line where all nuts and bolts are threaded in the same way with one in which threads of both handedness were needed and/or supnlied (61.15 . , , There are other advantages. An isotactic oolvmer . . can be assembled by a single stereospecific synthetase. A svndiotactic oolvmer (with a regular oattern of alternating Lhirality) wo;ld;equi;e one syAhetase to attach a D-intermediate to an L-form a t the growing head and another one to attach an L-intermediate to a D-form. Two more synthetases would be reauired for an atactic oolvrner containing DD and LL unions. Not only would it be iece&aryto line upthe right enantiomers. it would be necessary to orchestrate the activities of four synthetases. How much simpler to use one chiral form of amino acid and one synthetase! Even though that means producing a chiral polymer. We will never know just what sequence of events led, historicallv. ". to the develo~mentof life on earth. we mav never even achieve consensus as to the best speculative scenario, but i t seems clear that the common chirality of terrestrial life forms is consistent with, and to be expected from, the operation of Darwinian evolution. The biological advantages that monochirality bestows on evolving life forms are readily understood in terms of modern organic stereochemistry. The thermodynamic imperative toward racemization that characterizes most (but not all) nonliving systems does not apply to a biota derived from a single ancestral entityaand sustained by a steady input of energy. We cannot say whether supernatural intervention was, hktorically, iuvalved a t some point in the origin of life on earth-but we can say that i t was not required to generate the optical activity of living beings.
Noted added in oroof: A number of the ooints made here have recently beenmade by A. G. cairns-smith [Chem. Brit. 1986,5591.
Literature Cited (1)KnoKA. H.: Bsrghmm, E. 8. Seienea 1977,198,398. (2) Cloud.P."Casmm, EarthandMan";Vale University New Havm. 1978:aeaRowe, M. V. il Chorn. Educ. 1985,62.585. (3) Pleasant. L. G.:Ponnsmperuma, C. O r l g i Life ~ 1984,15.55. (41 Opsrin.A.I."TheOriginofLife": transl. byMorgulis,S.:Msemillan:NcvYork, 1938. (5) Calvin. M."Chemical Evolution":Oxford University: NevYork, 1969. ( 6 ) Saxan. C. "Enwelopedia Britannies", 15th ed.; Britannica: Chicaco. 1975:Vol10, pp
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Eigon. M.; Schuater, P. "The Hyporcyele": Springer-Verlag: Berlin, 1979. Cairna-Smith. A. G. '"GeneticTakaover and theMinerdOrigina of Lifc":Cambridge: Cambridge, 1982; Cairns-Smith.A. G. Sci. Amer. 1985. June.90. Gonzaln.0.J. J. Chem.Edur. 1985.62.503. B i d , J. G. Bull. Sor. Philomoth. L815.190, cited by L o w . T. M. "Optical Rotetory Pam"; hngmao8. Green: Landon. 1935: Dover Reprint, 1964. Paateur,L. C.R.Aeod.Sd. 1814,78,1515. Hunt,L.T.;Georae,D. G.;Yah,L.-S.:Dsyhoff,M. 0. OrigimLife 1984,14,657. Margulis, L. "Symbiosis in Cell Evolution"; h m a o : Sao h n e i s c o , 1981. Woese, C. R.; Debrunner-Vowbrink. B. A,; Oyabu, H.; Stsekebrandt,E.: Ludwig. W. Science 1985,229,762. Elias, W. E. J. Chem. Edue. 1912.49,448. Walker. D. C., Ed. "Origin of Optieal Activity in Nature": Elaevie.: Amsterdam. 1979. Brown, ME.: Buehansn, K. J.; Goasen, A. J Chom.Educ. I985,62,575:Smdden, R. B. J. Chem.Educ. 1985,62,653. House, H.0. "Modern Svnthetic Resetions". 2nd ed.: W. A. Bemiamin: Menlo Park. CA, 1972:pp 502-509.Csmpbell, K. N.;Campbell, B. K. Chem. RPU.1942.31.77. Knowle8, W.S.: Sabseky. M. J.: Vineyard,B.D. J. Chem.Soe.,Cham. Comrmm. 1912,
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Jsdues. J.; CoUet. A.: Wilen. S. H. "Enanfiomers. Reematas and Resolutions":
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Pinrock. R E . Udaor,. K 11 .I Amrr Chrm Sw 1971. 93, 1291: P i m a t . R. E.: Prk.u
