by Pross, Addy
3. Molecular self-replication of template-like molecules is an established chemical reaction and is kinetically unique. Being autocatalytic, self-replication can lead to dramatic exponential amplification of that template-like molecule until resources (building blocks from which the chain is composed) are exhausted.
The discovery that self-replicating molecules exist is highly significant because, as we will see, the existence of such molecules can form the basis for understanding how life emerged, how inanimate matter began the long and arduous road from simple beginnings to the extraordinary complexity that is life. Of course that single replicating molecule, whether RNA or some other related structure, does not in itself constitute life, not even simplest life. It is, after all, just a molecule. In fact, in many respects the reaction of self-replication is a chemical reaction governed by the rules of chemical reactivity, just like any other reaction. But there is something special about this self-replication reaction that leads us to believe it was the likely starting point for life. I have already indicated that self-replication, being autocatalytic, is kinetically unique in that it can lead to dramatic amplification, just like the effect of doubling the number of grains of rice on a chess board. We will now see how that kinetic power can lead us in quite unexpected chemical directions, in fact, to the establishment of a totally separate and distinct branch of chemistry, so distinct in its character that it goes under a separate label—biology! But in order to do so we first need to delve a little deeper into a basic concept of nature, one we have briefly mentioned in the context of the Second Law of Thermodynamics—the concept of stability.
The nature of chemical stability
The concept of stability is a relatively straightforward and unambiguous one: an entity is stable if it persists, if it maintains itself without change over time. But here’s the remarkable thing—within the material world stability can be of two fundamental and very different kinds—static and dynamic, one very obvious, the other rather less so. Static stability is the more obvious kind. For example, water, being a stable material in a thermodynamic sense, if suitably isolated, will remain unchanged over time, even over extended periods of time. Thermodynamic stability, which we discussed earlier, exemplifies this static kind of stability.
But there is another kind of stability—a dynamic kind, which is quite different to the static kind. Think of a major river, say the River Thames passing through central London. Its history can actually be traced back some 30 million years when it was a tributary of the River Rhine, but its current path and appearance are thought to have remained relatively unchanged for several thousand years. Accordingly, the River Thames, as an entity, may also be classified as quite stable. But in this case the kind of stability involved is very different from systems that are statically stable. The water that defines the River Thames is not the same water, but is changing all the time. The river we see today is in a sense a totally different river from the one we saw last time we looked. Its stability is a dynamic stability—the water that defines the river as a recognizable entity is constantly changing. A water fountain or a waterfall also manifests this dynamic kind of stability—the fountain (or waterfall) is stable (as long as the supply of water remains uninterrupted) but the water comprising that fountain (or waterfall) is being turned over continually.
So what does the stability of rivers, waterfalls, fountains, and the like, all displaying stability of a dynamic kind, have to do with chemical reactions, at least some of them? The answer is, quite a bit. Let’s return to the reality of molecular replication. The process of molecular replication, because it can exhibit exponential growth, is unsustainable, just like doubling the grains of rice on a chess board. If one single molecule were to replicate 160 times it would (only in principle, of course) devour resources equal to the entire mass of the earth! What that must mean is that any replicating system (whether composed of replicating molecules, rabbits, or some other group of replicators) that is stable, can only be stable if its rate of formation is balanced (more or less) by its corresponding rate of decay. In other words, in order for the replication reaction to be maintained for any extended period, the replicating system has to decay at a rate that is commensurate with its rate of formation. Under those circumstances the replication process, in principle at least, can proceed indefinitely.
But what would cause replicating entities of whatever kind to decay? If the replicator is chemical, say a replicating molecule, then that molecule will undergo competing chemical reactions, so such molecules will not survive for too long. RNA oligomers (an oligomer is just a chain-like molecule made up of component building blocks) and peptides, the prime examples of molecules capable of replication, are not too stable thermodynamically speaking and constantly undergo degradation processes. And if the replicating entity is biological—a bacterium or some multicell creature, the situation is much the same. In this case decay (now termed death) is also lurking close by. Lack of nutrition, chemical or biological attack, physical damage, apoptosis (programmed cell death), or other mechanisms, will eventually lead to the demise of all living things. The eventual death/decay of all living things, by whatever mechanism, will therefore balance the ongoing replicator formation and facilitate the dynamic stability of the replicating system.
The important point, however, is that if a replicating system is found to be stable over time, it is the population of replicators that is stable, not the individual replicators that make up that population. The individual replicators are being constantly turned over just like the water droplets that make up the river or fountain. In other words, the stability associated with a stable population of replicating entities, whether molecules, cells, or rabbits, is of a dynamic kind, just like that of the river or fountain. Think therefore of a stable population of replicating molecules as a molecular fountain. We will see how life’s dynamic character, a feature that has troubled modern-day biologists, derives directly from the dynamic character of the replication reaction.
In the context of chemical systems, static and dynamic forms of stability are very different. In the ‘regular’ chemical world a system is stable if it does not react. That is the very essence of stability—lack of reactivity. In the world of replicating systems, however, a system is stable (in the sense of being persistent and maintaining a presence) if it does react—to make more of itself, and those replicating entities that are more reactive, in that they are better at making more of themselves, are more stable (in the sense of being persistent) than those that aren’t. This is almost a paradox—greater stability is associated with greater reactivity. We therefore call the kind of stability associated with replicating systems a dynamic kinetic stability. Its stability is dynamic for the reasons we have outlined, but we need to introduce an extra term in the description—the word ‘kinetic’—to distinguish it from the dynamic stability of fountains, rivers, and the like, which is physical, and not chemical. For replicating systems the rate at which the replicating system makes more of itself, together with the rate at which it decays, are key parameters in determining the level of stability. High stability will be facilitated by a fast rate of replication and a slow rate of decay since that will lead to a large population of replicators. To our chagrin, mosquitoes and cockroaches are highly stable in this dynamic kinetic sense—they are extremely efficient in maintaining a large population, whereas pandas, for example, are much less efficient. Indeed, low dynamic kinetic stability for a replicating entity, whether due to slow replication or fast decay, may well lead at some point to the population of that replicator becoming extinct.
I have described here the existence of a distinct kind of stability quite different from the regular stability with which we are more familiar, so given the existence of two kinds of stability, one might ask which is the preferred one, which stability is inherently the more ‘stable’? A definitive answer to the question is actually not possible—it’s the old apples and oranges problem. The two kinds of stabilities are not directly compara
ble and in fact one of them, dynamic kinetic stability, is only quantifiable in a very limited way. But intuitively we might suspect that static stability, the one based on a lack of reactivity, is inherently the preferred kind of stability, the one likely to be more enduring—wouldn’t it? Well, not necessarily! In examining the world around us we are led to a surprising conclusion. Mt. Everest, for example, a statically stable entity (ignoring tectonic movements), is thought by geologists to have existed for some 60 million years, so clearly static stability can be very substantial. But cyanobacteria (blue-green algae), a very ancient life form, appear to have continuously populated the earth for several billion years, with little, if any morphological change. Biologists might argue over the period that they have remained unchanged, whether it is closer to 2.5 or 3.5 billion years, but there is no argument that cyanobacteria have been around for several billion years. Now that is stable! Of course, we are speaking here of a dynamically stable system—the cyanobacteria alive today are not the same ones that were alive several billion years ago. But through ongoing replication they have maintained a continual presence on this planet for an extraordinarily long period of time. Let us be clear: despite the dynamic character associated with replicating systems, their form of stability should not be underestimated; it is able to encompass time frames that cover a significant fraction of this planet’s 4.6 billion-year lifetime.
Our discussion till now has made clear that (static) thermodynamic stability and dynamic kinetic stability are applicable to different systems and are quite distinct in their nature. But the fact that there are two very different kinds of chemical stabilities has profound implications for both the physical and chemical characteristics of systems within each of the two classes. This is because the rules governing transformations for chemical systems belonging to the two different stability types are necessarily different. In effect there are two chemistries out there! One of the chemistries is just ‘regular’ or traditional chemistry, which has been studied for several centuries and is well understood—a mature science. The other is replicative chemistry, the chemistry of replicating systems. This other chemistry, part of a new area of chemistry recently named ‘systems chemistry’, is still in its infancy.29 Systematic study in the area was only initiated some twenty-five years ago and many chemists remain unaware that such a field even exists. Let us now flesh out the nature of this ‘other chemistry’, why it comes about, what are some of its prime characteristics, and how this new field is providing the basis for the building of bridges between the sciences of chemistry and biology.
Rules governing replicator transformation
In 1989, Richard Dawkins alluded to a fundamental law of nature which applies to both the biological as well as the broader physicochemical world: the survival of the most stable.30 Steve Grand, in his 2001 book, Creation, expressed it somewhat differently: Things that persist, persist. Things that don’t, don’t.31 This sounds like a tautology, and in some respects it is. But there is an important message present within that seemingly trite statement. Once it is (empirically) evident that matter is not immutable, that it is susceptible to chemical change, then it necessarily follows that matter will tend to be transformed from less persistent to more persistent forms, in other words, from less stable to more stable. Persistent forms don’t tend to change because they are… persistent. And, of course, less persistent things do tend to change because they are less persistent. So matter, by definition one could say, tends to become transformed from less persistent to more persistent forms, or couched in stability terms, from less stable to more stable forms. As a matter of fact, that is what chemical kinetics and thermodynamics is all about—being able to explain or, better still, predict the likely reactions of chemical systems in their search for more stable forms. And what is the central law that governs such transformations? The Second Law. A mixture of hydrogen and oxygen gases readily reacts to give water because the hydrogen-oxygen gas mixture is unstable, whereas the water product is stable. When matter reacts chemically, it reacts so as to become transformed from thermodynamically less stable reactants into thermodynamically more stable products.
But what happens in the chemical world of replicators, in the world of replicating molecules, for example? What rule governs transformations within that world? Of course a replicating molecule may undergo chemical reactions in which it is converted into one or more non-replicating molecules. However, we are not concerned here with those kinds of reactions. They are covered by the rules governing chemical reactions generally. The reactions that are of special interest are those in which a replicating molecule (or set of molecules) is transformed into some other replicating molecule (or set of molecules). It is these reactions, which address the nature of replicating systems as a class, that we must further explore. As we will discover, it is this very special class of molecules that offers unique potentialities. And now to the essential point: given that the kind of stability applicable in the replicating world is dynamic kinetic, not thermodynamic, the rule that effectively controls transformations within the world of replicators is not the Second Law, but one that is expressed in terms of dynamic kinetic stability. The rule is simply stated as follows:
Replicating chemical systems will tend to be transformed from (dynamically) kinetically less stable to (dynamically) kinetically more stable.
That selection rule is in some sense an analogue of the Second Law, the selection rule in the regular chemical world. In both worlds chemical systems tend to become transformed into more stable ones, but as the two worlds are each governed by a different kind of stability, the selection rule in each world is different—thermodynamic stability in the ‘regular’ chemical world, dynamic kinetic stability in the replicator world. As we will now see, the implications of those distinct selection rules are profound. But before we discuss those implications, is there any evidence for the distinctly different selection rule in the replicator world that is being proposed here? Yes, there is. Back to Sol Spiegelman and his remarkable RNA replication experiment conducted over forty years ago.
In describing Spiegelman’s landmark experiment earlier in this chapter, I neglected to tell the whole story. It is true that an RNA strand when mixed with its component building blocks (and added enzyme catalyst) undergoes a self-replication reaction. But something else takes place as well, something of considerable significance. Replication may on occasion occur imperfectly, in that the wrong nucleotide segment will attach to the template. For example, a C nucleotide, rather than an A nucleotide, will attach to a U segment on the template chain. Thus, on occasion, imperfect replication will lead to the formation of a mutant RNA strand. In other words, over time the solution will begin to consist of both original RNA strands as well as mutated ones. And here Spiegelman made a remarkable observation. Over time the solution began to be populated by mutant RNAs that replicated more rapidly than the original RNA strand. In fact the original sequence after some time may even disappear from solution! In other words, a process akin to Darwinian selection was found to take place at the molecular level—the RNA strands evolved. Since short RNA strands replicate more rapidly than longer RNA strands, the initial strand composed of some 4,000 nucleotides began to shorten and eventually ended up with just some 550 nucleotides. The replicating prowess of the short strand was so dramatic it was termed Spiegelman’s Monster!
Before continuing it is important to note that the evolutionary process observed by Spiegelman is chemical in essence, not biological. An RNA strand in no way constitutes a living entity—it is a molecule; admittedly a biomolecule, meaning that it is a molecule of the kind normally found in living systems, but a molecule is a molecule is a molecule. And the fact that a slowly replicating molecule tends to evolve into a more rapidly replicating one is due to chemical factors, chemical kinetics to be precise. Nothing biological here—just chemistry. While this is not the place to go into a detailed kinetic analysis of the competition between two replicating molecules, the bottom line is easy to
state. When a number of different replicating molecules all compete for the common building blocks from which they are constructed, the faster replicators out-replicate the slower ones so that over time the slower replicators will tend to disappear. What effectively happens is that slower replicators are replaced by faster ones in precise agreement with the general selection rule for replicating entities that was specified above.
As a final point it is important to ask how the two stability kinds, static and dynamic kinetic, interrelate. The statement that the replicating world is governed by the drive toward greater dynamic kinetic stability, though correct, needs to be qualified, and that qualification can be expressed through the metaphor of Russian dolls. Although the replicative world is governed by an analogue of the Second Law, no physical or chemical system can avoid complying with the Second Law itself. That is the grand and comprehensive rule, the one governing all transformations in the material world. So how can two different laws operate simultaneously on the one system? The answer is that the Second Law analogue governs replicating systems within the constraints of the Second Law itself, just like Russian dolls that fit one within the other. A simple example from everyday life may clarify the issue.
Your car breaks down and you ask your mechanic to explain the reason for that breakdown. If he mumbles something about the Second Law of Thermodynamics as the explanation for the breakdown, you’d be quite frustrated, even though his explanation was entirely correct. Correct, but quite unhelpful. The direction of all irreversible processes is governed by the Second Law, so whatever event caused your car to break down it was in a fundamental way governed by the operation of the Second Law. So why was the answer unsatisfactory? Because there are rules that govern car function—how engines operate—that sit within the more general framework of material happenings as expressed by thermodynamics. The Russian doll of engine function sits within the bigger thermodynamic doll. To fix your car you want to know what happened within the context of the smaller doll, the one that deals specifically with engine function. Did the fuel line become blocked or did the timing belt break? The Second Law, the more global explanation, though correct, is of no practical use. And so it is with replicating systems. Stable replicating systems operate according to the rules that govern replicating systems, as described earlier in this chapter, but that specific behaviour is not independent of the Second Law. Rather, it operates within the general constraints that the Second Law places on all material systems. There is no contradiction then between the two rules. The underlying message in the Russian doll metaphor is that we will be better able to understand reactions in the replicative world by considering the rules that govern that world, rather than the more general thermodynamic principles that govern all material systems. Stating that the reactions of replicating molecules and biological evolution, in general, are governed by the Second Law is formally correct, but very much like saying that that is the reason your car broke down. Correct, but not particularly helpful!