What is Life?:How chemistry becomes biology

by Pross, Addy

  There is a moral to the above story: some characteristics of undeniable scientific interest are inherently difficult to quantify, or are even unquantifiable. Attempts to quantify the unquantifiable will be unrewarding and may only lead to confusion. The above discussion relating fitness to its underlying chemical term, DKS, makes clear why attempts to quantify fitness have proved so elusive. Not everything that counts can be counted. In addressing the concept of fitness, context is everything.

  Despite the difficulties we’ve discussed in our ability to formally quantify DKS, two crude measures of DKS are actually available. These are the steady-state population number for a given replicating entity and the length of time that the replicating population has managed to maintain itself. A large steady-state population of some life form means that it is more readily able to withstand environmental changes that may undermine its existence. By contrast, if the population size of some living form is low, then clearly that population is vulnerable and may become extinct. On that basis it is reasonable to conclude that cockroaches and mosquitoes are more stable (in a DKS sense) than pandas. Cockroaches and mosquitoes are unlikely to become extinct in the foreseeable future, while the future of pandas is far less certain. Replication is ultimately a numbers game. The time dimension can also be a useful gauge of DKS. Cyanobacteria, which have maintained a continuing presence on our planet for several billion years, would of necessity be classified as stable, remarkably so. Modern humans, by comparison, have only existed for some 150,000–200,000 years, so our long-term stability is far less assured. No matter. Appreciating that fitness is the biological expression of a particular kind of stability helps place biology in a more physical context, and assists in our goal of merging the biological and physical sciences.

  Survival of the fittest and its chemical roots

  Having established the connection between fitness and stability we can now seek the chemical equivalent of that quintessential biological phrase ‘survival of the fittest’, or its more modern biological expression, ‘maximizing fitness’. This will prove of importance since this connection will lead us to the profound realization that the entire evolutionary process illustrated in Fig. 6, i.e., both the emergence of life from inanimate beginnings, as well as the evolution of simple biological systems into more complex ones, may be associated with an identifiable driving force. The fact that a driving force for that entire process might be identifiable should not be a great surprise—that, after all, is nature’s way. In nature many processes are associated with a driving force. Flowing rivers, rainfall, avalanches, falling apples, are all associated with the gravitational force, while the driving force for all chemical reactions is just the omnipresent Second Law of Thermodynamics. Of course the term ‘force’ needs to be interpreted broadly, in line with our comments on pattern recognition in chapter 3. Forces do not have to be visible to be identified. The existence of a force is postulated through empirical recognition of its action. In the case of replicating systems and their clear tendency to become transformed into more effective replicating systems, the driving force can now be identified as the drive toward greater DKS. In other words, the biological term ‘maximizing fitness’ is just the biological expression of the more fundamental and more ‘physical’ concept—maximizing DKS. So let’s equate them:

  maximizing fitness = maximizing DKS

  In simple language that just means that replicating systems tend to become more successful replicators—those that can maintain themselves more effectively over time. In this light, abiogenesis and biological evolution, the two phases of Fig. 6, are both an expression of the drive toward greater DKS. Thus the transformation of inanimate matter to simple life should not be viewed as a collection of haphazard and contingent chemical events, but rather as a coherent process governed by an identifiable driving force. That same force operates during the so-called abiogenesis phase as well as the biological phase, and that is why the two phases should be viewed as one. The driving force for evolution is not natural selection, as is suggested from time to time. Natural selection is a rudder, not a driving force. Natural selection, as its name states, just selects. Natural selection (or its chemical equivalent, kinetic selection) helps steer the replicating population toward higher DKS by the continual elimination of those entities in the population that contribute to a lowering of its DKS. And that is true along the entire evolutionary road, from the population of simple (but unidentified) replicating entities which heralded life’s tentative beginnings, right through to complex life.

  We have specified the driving force for evolution, and already identified a primary mechanism for change—complexification. As we discussed earlier in this chapter, complexification is a main (but not sole) mechanism by which replicating systems enhance their DKS. That is not necessarily obvious if one looks at evolutionary changes on short time scales, just as one cannot see the ageing process in humans on a day-to-day basis. But if we step back and look at the evolutionary process over an extended period of time what we see is quite unmistakable. It is increasingly clear that life started off simple—some highly unstable replicating system (a replicating molecule or small replicating network)—and ended up complex, with multicell replicators—elephants and the like—roaming around.60 That complexifying transformation was no fly-by-night operation—it took place over literally billions of years. But its undeniable presence all around us is unequivocal testimony to the reality of the process. From microscopic beginnings in some unknown location on the prebiotic earth, the process overwhelmed the entire planet with life forms of all sizes, all linked together in an awe-inspiring ecological network. Let us now consider that complexification process in more detail.

  That initial replicating system on the prebiotic earth must have been highly fragile. It takes a sophisticated chemist in a sophisticated lab to induce a replicating molecule to replicate. Replicating molecules can be quite temperamental, and it is no easy matter to get them to replicate. Ask any systems chemist! But take any small sample of soil in your backyard, look carefully, and what you find are billions of bacteria replicating away quite happily—no chemist in charge, no lab, no postdocs, no equipment. Bacteria are highly robust and effective replicators. Bacteria are highly stable in a DKS sense and that high stability has come about through the long evolutionary process of complexification. In other words, a step-by-step process of complexification led from some replicating system, initially fragile and highly unstable, to the highly stable, highly complex, replicating entity that is a bacterial cell. We don’t know and will likely never know the identity of that first replicating system or its first tentative steps toward robust life—that historic information is shrouded in the mists of time. However the nature of the first step on that long road to complex biological systems is clearly illustrated in Gerald Joyce’s two-molecule RNA system which replicated more effectively than any single RNA molecule.57

  Information and its chemical roots

  The concept of information permeates all of modern biology. In fact entire books have been written on the topic, and for good reason. The concept of information, as manifest in the sequence of the nucleotide building blocks that make up the DNA molecule, has been central in our understanding of the key processes of molecular biology. In that sense DNA replication can be thought of as the process that provides for the preservation of information, one in which genetic information is passed on from generation to generation. And how is this information expressed? Transcription and translation, those key processes on which the central dogma of biology rests, deal precisely with that issue—the manner in which the information in the DNA sequence is somehow translated into the multitude of unique protein structures on which much of life’s functionality is based. But here’s the puzzle. Open a chemical textbook and you will most likely not find the ‘information’ word in there at all. Chemists talk about reactivity, selectivity, stability, reaction rates, catalysis, and many other chemically useful terms, not about information. So how can that be
? If biology is just a complex kind of chemistry, and information is central to biology, then information must exist within chemistry as well. If not, where did the information within biological systems come from?

  To answer the above questions, let us now think about DNA’s reactions in chemical rather than biological terms. That wondrous DNA molecule, through the process of replication, acts as an auto-catalyst. DNA is an autocatalyst because it catalyses its own formation. The building blocks that go to make up a second copy of DNA will not proceed to do so unless one DNA molecule is already present, one that serves as a template, and thereby facilitates that autocatalytic behaviour. But, of course, DNA does not just catalyse its own formation. Through the processes of transcription into messenger RNA and the subsequent translation of the messenger RNA sequence into an amino acid sequence (proteins), it also acts as a catalyst, a catalyst for the synthesis of other materials. In the absence of that DNA molecule with its specific sequence, the transformation simply could not occur. The precise sequence of the DNA segment that is expressed through operation of the ribosomal machinery determines the precise structure of the protein that is obtained. Change the DNA sequence and you end up with a different protein structure. What that means therefore is that DNA is not just an autocatalyst, but also a highly specific catalyst. A particular DNA segment sequence corresponds to a particular protein, a different sequence would correspond to a different protein. A moment’s thought suggests therefore that the term ‘information’ in its biological context is just ‘specific catalysis’ when considered in a chemical context. The different jargons employed by the two sciences can create divisions that are not actually there. So in a chemical context what has taken place over the evolutionary time frame is that some autocatalyst endowed with catalytic properties evolved in such a way as to enhance those catalytic properties. Initially that primordial nucleic acid autocatalyst might have just exhibited the ability to catalyse the formation of simple peptides as a precursor to some primitive translation process. However, over time, and with the establishment of the genetic code, the efficiency and the specificity of that catalytic capability would have continually increased, driven by the DKS imperative. The biological phenomenon of information generation is nothing other than the chemical phenomenon of establishing and enhancing specific catalytic function.

  A comment regarding the connection between ‘information’ and the Second Law is now called for. The highly ordered sequence of the DNA molecule is of course thermodynamically unstable. The Second Law dictates that ordered systems tend to become disordered so information tends to be degraded, not created. That might suggest that the generation of information out of nowhere would contradict the Second Law. But of course there is no contradiction. Just as my writing of this book creates information (hopefully), the process of evolution can also create information, provided, of course, the appropriate energy cost is paid. That’s where life’s metabolic processes come in—to supply the required energy to keep life’s machinery going and maintain life’s far-from-equilibrium state. So the question of how information emerged from non-information is just a rephrasing of Schrödinger’s question of how unstable, far-from-equilibrium systems, emerged in the first place. We will deal with that question shortly.

  Toward a general theory of evolution

  Based on the previous arguments we can now piece together the central elements of a general theory of evolution, one that is applicable to both chemical replicating systems as well as biological ones. Like its biological counterpart, its central elements revolve around replication, mutation, and selection, but as we have indicated, the process of complexification needs to be incorporated into the general scheme so that the causal sequence in evolution becomes: replication, mutation, complexification, selection, evolution.

  Let us then begin by specifying the why and the how of evolution. The why is the driving force for the process—the drive toward greater replicator DKS. The how is the mechanism for that process and would have comprised the steps previously mentioned—replication, mutation, complexification, selection. The process is initiated by the emergence of some oligomeric replicating entity susceptible to imperfect replication. An RNA molecule, or one related to it, illustrates the kind of molecule that would have been able to initiate the process, though other possibilities cannot be excluded. In any case, its precise identification would not be necessary in seeking the principle of the process. Once that molecule begins to self-replicate, either on its own or within a minimal network, it would tend to enhance its stability (of the dynamic kinetic type, as we have described earlier) due to the driving force that operates within the world of replicating entities—the drive toward greater DKS. And now to the second step. Replication occurs with occasional mutations thereby creating a diversity of replicators. Moreover, if one includes horizontal gene transfer as an additional mechanism leading to genetic diversity, then it is apparent that genetic variation does not have to derive solely from the replication step.

  And now to the complexification step. Any molecular replicator (or replicating network) once formed would tend to interact with other available materials potentially leading to more complex replicators. Importantly, that process of complexification would have been initiated from the outset, at the molecular level, the moment the system was governed by that other stability kind, DKS. Of course, complexification would not need to be restricted solely to members of the class of replicating molecules. Replicating sequences capable of catalysing the formation of other chemical classes, e.g., peptides, exhibiting catalytic activity with respect to the replication reaction itself, would further add to the process of complexification and evolution toward more stable replicating systems. Complexification would therefore entail a co-evolutionary process in which non-replicative molecules could also partake in the building up of increasingly complex replicative networks. Such a process would continue unabated as long as the system as a whole remained holistically autocatalytic. Thus it is complexification, through the establishment of increasingly complex chemical networks, that would be the primary mechanism for the enhancement of replicator DKS and the generation of stable replicating systems.

  And finally selection. Once a population of diverse replicating systems is established then (kinetic) selection would act to change the proportion of replicators within the population to those able to better contribute to the population’s DKS. Of course the result of that process of continuing cycles of replication, mutation, complexification, selection, is evolution.

  Let us now return to the issue of what drives evolution. Our earlier discussion, where ‘fitness maximization’ has been translated into ‘DKS maximization’ helps place biology squarely in the physical-chemical world where ultimately it should belong. Just as in the ‘regular’ chemical world the drive of all physical and chemical systems is toward the most stable state, in the replicative world the drive is also toward the most stable state, but of the kind of stability applicable within that replicative world, DKS. We see then that the material world can in some sense be subdivided into two parallel worlds—the ‘regular’ chemical world and the replicative world. Transformations in the ‘regular’ world are governed by the Second Law, and in the replicative world by what could be considered to be an analogue of the Second Law. So, as is manifestly evident, we live simultaneously in two discrete chemical worlds—two worlds governed by different kinds of stability and therefore expressing two quite distinct chemistries. As we have seen, one of these chemistries, the chemistry of the replicative world, is called biology.

  How did a metabolic (energy-gathering) capability come about?

  But now the unavoidable question must be asked. How can there be two laws that govern chemical transformation? Isn’t this a contradiction? How can there be two kinds of stability? What happens when these two kinds of stability pull in opposite directions? Which would win? The answer is quite surprising. Even though the Second Law is the ultimate law, the one whose directive cannot be ignored, it
is actually the Second Law analogue that wins! Let’s see how this comes about. In doing so we will obtain insight into the issue that troubled Erwin Schrödinger—how could far-from-equilibrium systems have emerged naturally?

  It is true that no physical or chemical system can undergo change contrary to the strict requirements of the Second Law. To do so would be equivalent to proposing that balls spontaneously roll uphill, and they don’t. However, if a replicating system were to acquire an energy-gathering system, then nature could have its cake and eat it. It would be the existence of such a system that would enable the drive toward greater DKS to comfortably coexist with the strict requirements of the Second Law, despite the often opposing requirements of these two stability kinds. But how could this come about naturally?

  In a recent theoretical simulation, Emmanuel Tannebaum and Nathaniel Wagner, two colleagues in the chemistry department at Ben Gurion University, and myself, have demonstrated that a replicating molecule that underwent some chance mutation that enabled it to capture energy, say, light energy, in a primitive kind of photosynthesis, would be able to out-compete a molecular replicator that lacked such a capability and drive it to extinction.61 This could even be true if the energy-gathering replicator was intrinsically slower! How can that be? The process of replication requires that the building blocks from which the molecular copy is composed be chemically activated. Activation is necessary to enable the building blocks to link up once they have locked into place on the template molecule. That’s a Second Law requirement and it must be obeyed. However activated (high-energy) building blocks are likely to be in short supply compared to unactivated (low-energy) ones. So a non-metabolic replicator (without an energy-gathering capability) would quickly use up the available quantity of activated building blocks at which point the replication reaction would cease. If, however, the replicating molecule is metabolic (i.e., it possesses an energy-gathering system), then that replicating molecule, by acquiring energy, could transmit that energy to the building blocks that have attached to it, thereby activating them. In other words, the existence of an energy-gathering capability within the replicator molecule can effectively increase the availability of activated building blocks, thereby facilitating the replication reaction for the metabolic replicator.