When I was a student, around 1940, chemists had a clear understanding of the nature of molecules—maybe even too clear. The molecule, “the smallest portion of matter that preserves the properties of the substance it belongs to,” was tangible and concrete, a small model. Physicists already knew a lot about the functions of the wave, the vibrations of atoms, the rotations and degrees of independence of the whole molecule and its component parts, the nature of the valence. Organic chemists, however, were reluctant to follow them into this terrain. They remained fascinated by stereochemistry, a relatively recent conquest. Stereochemistry is the branch of chemistry that studies precisely the properties of the molecule as an object, having thickness, bulges and recesses, bulk—in short, an object with a form.
It hadn’t been a short journey. The concept of molecular weight had been precisely defined since the middle of the nineteenth century: the weight of the molecule corresponded to the sum of the weights of its atoms and could be determined by simple techniques available to all laboratories. Elemental analysis also had a solid foundation, and so it was possible to know which and how many atoms made up the molecule. But we would not venture to represent the molecule’s structure: it was conceived as a bundle, a shapeless cluster. We already knew pairs of compounds, such as acetone and propionaldehyde, or diethyl ether and butanol, which had the same composition but entirely different chemical and physical properties. This phenomenon was given a beautiful Greek name (“isomerism”) long before the analytical methods of the time could explain it. We guessed that it must be a permutation, but our understanding of the spatial arrangement of the atoms within a molecule was still too vague.
Then even more unusual pairs, or sets of three, were observed. Their members were identical not only in their composition but also in all their properties, except two. One member rotated the plane of polarized light to the right, the other to the left, and the third (sometimes) did not rotate it at all. For instance, in nature or in fermented products a right-handed lactic acid and a left-handed one were observed, while the acid obtained in the laboratory was always inactive. Moreover, the crystals of the right-left pairs often showed a strange asymmetry: one set could not be superimposed on the other, but was its mirror image, just as the right hand is the mirror image of the left.
The phenomenon whetted the robust scientific appetite of the young Pasteur. As a matter of fact, this man of genius, who was to revolutionize pathology, was not a medical doctor but a chemist. It was understandable that products made by synthetic processes were inactive in polarized light: optical activity depended on asymmetry, while in a laboratory, from symmetrical reagents, one could obtain only symmetrical products. However, how do we explain the asymmetry of natural products? No doubt it must come from a preceding asymmetry, but where was the original asymmetry?
Pasteur and all his interlocutors understood that this challenging problem was far from purely academic. Not all asymmetrical substances as described here belong to the living world (for instance, quartz crystals are asymmetrical); but all the main actors of the living world (proteins, cellulose, sugars, DNA) are asymmetrical. Right-left asymmetry is intrinsic to life; it coincides with life; it is unfailingly present in all organisms, from viruses to lichens and oak trees, from fish to man. This fact is neither obvious nor unimportant; it challenged the curiosity of three generations of chemists and biologists and it gave rise to two big questions.
To cite Aristotle, the first question is that of the final cause—that is, in modern terms, the question of the adaptive utility of asymmetry. Let’s confine ourselves to proteins, the life structures where the phenomenon is expressed in its clearest and most extensive form. As we know, the long protein molecule is linear; it’s a filament, a rosary of hundreds or thousands of beads. Not all the beads are the same; they consist of about twenty relatively simple compounds, basically the same for all living beings, called amino acids. They can be compared to letters of an alphabet that are used to compose very long words of a hundred or a thousand letters. Each protein is one such word; the sequence of amino acids is unique for each protein, determining its properties, and also the way in which the filament can fold. Now, although all amino acids (with one exception) have an asymmetrical molecule, they can all be represented by just one of the two diagrams reproduced here and differ from each other only by the nature of the R group. They are all “left-handed,” as if they had all come out of the same mold, or as if something had discarded or destroyed their mirror images—that is to say, their right-handed twins. But each protein must possess a precise identity in every one of its beads; if just one of them were to change configuration, the protein would change form. Thus we can perceive an advantage in the fact that only one of the two mirror-image forms of each amino acid is available in the biosphere. If just one of the thousands of beads in a protein chain were to be replaced by its mirror image, many of the subtlest properties of the protein would change fundamentally—in particular, its immunogenic behavior.
But that asymmetry, so carefully transmitted by the living cell, is difficult to obtain and easy to lose. Whenever the chemist tries to synthesize an asymmetric compound, he obtains a mix of the two mirror images in exactly equal quantities, thus inactive in polarized light. It is possible to separate the mirror images, but only and always with instruments or devices that are asymmetrical. Conceptually, the simplest method goes back to Pasteur. The crystals of certain right-handed compounds can be distinguished by sight from their left-handed analogs in the same way that a moderately trained eye distinguishes a right-handed screw from a left-handed one, and they can be separated manually—but the human eye, and all that lies behind it, is asymmetrical. A second method, pertaining to chemists, consists in combining the mixture of mirror images with another asymmetrical compound, for instance the mixture of the two lactic acids R and L with a natural alkaloid R (the alkaloids with asymmetrical molecules also are usually found in nature in just one of two forms). It is clear that the R-lactate of R-cinchonine is the mirror image of the L-lactate of L-cinchonine, and not of the L-lactate of R-cinchonine. In short, an RR compound is a mirror image of the LL compound; therefore, the two will have identical physical characteristics. However, the LR compound will have different properties and it will be easy to separate it from RR, for instance by fractional crystallization. Besides, it often happens that an R-acid agrees to combine with an R-base but not an L-base, in the same way that a right-handed screw does not fit into a left-handed nut.
The opposite path, that of canceling the asymmetry produced by nature instead of imitating it, is infinitely easier; from the point of view of energy, “it goes downward.” Outside the living organism, asymmetry is fragile; prolonged heating or contact with certain substances with a catalytic effect is enough to destroy it. More or less rapidly, half of the asymmetrical compound is transformed into its mirror image; the order of asymmetry has turned into the disorder of symmetry (or counterbalanced asymmetry), just as when we shuffle a deck of cards arranged by suit or color. Extremely slowly (on a scale of millennia) this process also occurs spontaneously and at a normal temperature, so that it is used to date items that in the past were part of living organisms, such as bones, horns, wood, fibers, and the like; the more advanced the loss of asymmetry, the older the object.
In the face of life’s maniacal preference for asymmetrical molecules, Stanley Miller’s famous experiment, it seems to me, loses some of its impact. In 1953, Miller subjected a mixture of water, methane, ammonia, and hydrogen to electrical discharges for several days, trying to simulate the conditions of the primordial atmosphere jolted by lightning. He obtained several well-known amino acids, thus confirming that for their synthesis the complex and selective methods until then followed by chemists were not indispensable. The fundamental building blocks of proteins “are eager” to form; they form almost spontaneously from chaos provided they are given energy, even in a crude form. Amazingly, some complex DNA components are also formed along with them. However, Miller and his numerous followers always obtained symmetrical products—i.e., balanced mixtures of the respective mirror images. The building blocks of life are eager to form, but asymmetry isn’t.
I have not yet mentioned an odd and troubling fact. I do not know what fool first said that “the exception proves the rule.” It does not prove it at all; it weakens it and calls it into question. Now, the rule according to which the amino acids of all living beings are in an optically active form (that is, are not mixtures of mirror images) knows no exception so far. There is, however, an exception to the rule according to which all these amino acids belong to the left-handed group. Amino acids of the right-handed group have been found in a few unusual, extremely marginal niches such as the skin of some exotic batrachians, in the cuticle of certain microorganisms, possibly (if confirmed, this finding should make us ponder) in some cancerous cells. But the right-handed amino acids of batrachians are not there by accident; they are part of substances carrying out intense physiological activity and if they are replaced by their normal—i.e., left-handed—mirror images, the activity ceases. Thus, they have a specific purpose, but we don’t understand it. And why do they exist only in those tissues, and not elsewhere? Maybe “once upon a time” their presence was more widespread, maybe they are the remnants of a different biochemical era? The exception does not prove the rule; it just confuses one’s ideas.
Thus, the asymmetry we are talking about is fragile. It is, however, unfailingly present in living matter, where it may be an evolutionary necessity to prevent spatial “errors” in the construction of proteins. We still have to consider the second, much more mysterious question, again with Aristotle: that of the efficient cause. Having recognized, or at least suspected, the usefulness of asymmetry (there are other asymmetries; the one under consideration here is called chirality—how easy it is to give Greek names to things we do not understand! Afterward, we feel we understand them better), we must ask ourselves where it could have originated. Evidently, in another asymmetry—but which one? Let’s examine the different hypotheses that have been, or could be, put forward.
1.The Earth rotates, and the Sun appears to rotate around the Earth. In the Northern Hemisphere and north of the tropic (and, similarly, south of the Tropic of Capricorn) the asymmetry exists, and it is conspicuous. For those looking southward, the Sun rises on the left and sets on the right. Certainly this has an impact, for example on the direction in which vine tendrils curl, and maybe also (I would kindly ask the experts to confirm or deny this) on the torsion of the trunks of many trees. It would be interesting to verify whether that direction is, at least as a trend, the same for all trees of a certain species in the Northern Hemisphere, and the opposite for the trees of the same species in the Southern Hemisphere. In fact, the “handedness” (the chirality, that is) of all phenomena related to the rotation of the Earth is reversed when we change hemisphere: the erosion of riverbanks, the preferred rotation of vortices, the direction of trade winds. This is a major obstacle to our first hypothesis; it would lead us to admit that life, or at least the asymmetry of life, regardless of how it originated, originated in only one of the two hemispheres and subsequently spread to the other when it was already linked. This is not impossible, but it is not appealing, either. It makes you think of a one-time phenomenon, a possibility that is not pleasing to many but very pleasing to a few. I will discuss it later.
2.Circularly polarized light is easily produced in a laboratory. It is less easy to explain in plain language what this light is; suffice it to say that it possesses the symmetry (or asymmetry) of the thread of the screw—that is, it’s “chiral,” and therefore can be right-handed or left-handed. This light, in suitable wavelengths, can be absorbed in different measure by one of the two mirror images of a pair, and can decompose it faster than the other; or it can act on the reaction mixture with which the chemist is trying to synthesize an asymmetrical compound. In both cases, the experiments have produced compounds that are unbalanced, and therefore optically active, although to a very small degree. Now, under certain conditions in nature the light reflected by water is circularly polarized. However, depending on the angle and the hour, there is an equal probability of its being right-handed or left-handed. We encounter here a difficulty similar to the one of the first hypothesis: Is it admissible that life exists thanks to a single, precise event; that the light reflected at a certain point in time by a certain puddle of water was instantly captured?
3.As I mentioned earlier, we find this asymmetry in nature in some inorganic crystalline structures, including, among
others, common quartz. There are right-handed and left-handed quartz crystals; in laboratory syntheses of asymmetrical compounds in the presence of quartz powder of homogeneous “handedness,” the resulting product was optically active. But, again, both right-handed quartz and left-handed quartz are equally abundant in nature. Actually, some researchers have maintained that right-handed quartz is more abundant, while others have denied it. Even in scientific research it’s easy to encounter individuals who replace what is with what they
wish for.
4.The Earth’s magnetic field, currently quite weak, possesses the required asymmetry, and possesses it at all points, without the reversals and the irregularity that weaken the previous hypotheses. Therefore it could have driven the same asymmetrical synthesis to the advantage of only one of the two opposites throughout the surface of the Earth. But here two other difficulties arise. First, as far as I know (but I have never had—nor do I have now, after so many years without practicing chemistry—any competence in this field; if anyone knows more, I will be glad to recant), there are no organic reactions sensitive to a magnetic field of reasonable intensity, except perhaps those involving iron, nickel, or cobalt atoms. Second, geologists are certain by now that the orientation of the Earth’s magnetic field reverses itself every few tens of thousands of years. Is it conceivable that this field, in remote ages, was vastly more intense, and constant for a sufficiently long time to incubate life?
5.The drama could have unfolded in different stages. A “primordial soup” like that obtained in vitro by Miller, made up in equal measure of right- and left-handed amino acids; then their aggregation into filaments, probably homogeneous, RRR . . . and LLL . . . ; the inception, according to one of the many hypotheses put forward, of life in a “two state” form, in which the two forms were unable to metabolize each other and were in competition; an extremely long Iliad, a silent contest lasting millions of years between right-handed life and left-handed life, which are enemies and incompatible; and, finally, in the absence of a reversion, the gradual prevailing of left-handed life up until the current situation, in which the enigmatic presence of right-handed amino acids in the skin of tree frogs may be just a minuscule survival. It is really a pity that fossils (except for the most recent ones, as I mentioned earlier) bear no trace of organic tissues; otherwise one could hope to find in them evidence of that old controversy, vaguely reminiscent of Zoroaster. Or maybe Radiolaria or Diatoma skeletons exist in chiral forms? This would be a good subject for a dissertation.
6.The hypothesis of the single event, of the una tantum, is not appealing and does not take us far, but it can’t be ruled out. We saw it peeping out as a premise of some of the hypotheses I outlined. A germ (a DNA molecule, a spore, a protein fragment) containing the foundation of asymmetry and of life could have fallen from space. This time-honored proposal was recently revived by no less than Francis Crick, who discovered the genetic code. However, it merely shifts the problem to a place and a time that are not accessible to us. We are left with the option of a single terrestrial event, unique, spontaneous, and random: not impossible but extremely improbable. You can’t build science upon single events, and so the discussion ends quickly, in an act of faith (or doubt). This option is made less irksome by a phenomenon studied by Giulio Natta (the 1963 Nobel Prize laureate) and described in his beautiful book Stereochemistry. If we build long chains of molecules—i.e., polymers—with no special precautions, we obviously obtain symmetrical and inactive products. On the other hand, if the polymerization is carried out in the presence of small quantities of an inert but highly asymmetrical substance, then the resulting polymer is also asymmetrical for its whole length. The inert substance acts as a sort of mold; from an asymmetrical mold we can obtain asymmetrical pieces in virtually unlimited quantities. Let’s resort to another comparison: by pressing dough on a perforated plate we obtain straight, very long spaghetti; but if the hole in the plate is crooked we obtain spaghetti that is equally long but curled, that is asymmetrical, leftward or rightward according to the shape of the hole. In other words, there exists, or we can imagine, a multiplying mechanism that could have magnified a local asymmetry, originating in one of the above-mentioned causes or in an infinitesimal fluctuation, and led it to the conquest of the world. Besides, hasn’t the recent discovery of isotropic and fossil radiation forced the majority of scientists to swallow, along with the Big Bang, the bitter philosophy of the unique event?
7.Chirality could have universal roots. I will not try to pretend, I will not expect to make you understand what I have not understood and what can’t be understood in the customary sense of the word, namely by resorting to visual models. Chirality might reside in the subatomic domain, where no other language is valid but the language of mathematics, where intuition does not reach and metaphors fail. One of the forces that link particles to each other, the weak interaction, is not symmetrical. The electrons emitted by certain radioactive disintegrations are unavoidably left-handed, without compensation. Therefore, all matter, even below the sensitivity of our measuring instruments, is optically active. The mirror images are never true mirror images; one of them, always the same, the left-handed one, is a bit more stable than its brother. The inactive mixtures obtained by the chemist are never exactly fifty-fifty; there is always an imbalance, in the range of one in a billion billion, but unfailing. It is small, but so is the key to a safe holding a ton of diamonds. If this is how things are (the debate is very recent, still hot) the entire universe would be pervaded by a slight chirality, and the deviations from parity would be only apparent; the “true” mirror image of the right-handed lactic acid, or of my right hand, would be not the left-handed acid or my earthly left hand but those in the distant realm of anti-matter. Later, through the eons, the magnifying mechanisms we spoke of would have acted on this infinitesimal inclination, on this tendentious whim. All right? For the moment, this is the answer we must settle for.
Maybe I should apologize; it’s difficult to be clear about things that are not clear to us, to make oneself understandable to the layman without boring or shocking the experts. Moreover, I know I have strayed into a field that is not (any longer) mine. It was, however, the subject of my dissertation. I have returned to it with reverence, some regret, and the fear of having made mistakes; you pay a price for years of retirement.
I have tried to bring up to date a problem that remains current in spite of the innovative hypothesis that I attempted to describe last, with the reverence of the outsider, one who stops at the threshold of the temple. Maybe it is a “pointless” problem, even if it is not always pointless. If, for instance, pharmacologists had paid more attention to the question of optical isomerism, the tragedy of thalidomide could have been avoided. This product has an asymmetrical molecule; it was originally put on the market as a “raceme,” that is, a balanced mixture of the two mirror images as obtained from synthesis. Subsequent research—such as by Blaschke et al., Arzneimittel-Forschung (1979)—on rats showed that only the left-handed mirror image was teratogenic; the right-handed one had a normal tranquilizer action. Had the two mirror images been separated and examined separately, nothing would have happened.
At any rate, this is a fine and fertile problem. Unlike philosophical problems, this one, I think, will not remain unresolved forever; even minor discoveries may help. Are the amino acids apparently found in meteorites optically active? Has anyone tried to synthesize in a magnetic field an asymmetrical molecule containing iron? To me, the discovery of the chirality of the universe, or just of our galaxy, seemed overwhelming—dramatic and enigmatic at the same time. Does it have a meaning? And if so, what meaning? How far does it take us? Is it not a “game of dice,” the same that Einstein refused to attribute to God?
Prometeo 2, no. 7 (September 1984)