by Pross, Addy
Before beginning the discussion let’s make sure that the terms ‘metabolism’ and ‘replication’ are adequately defined. Broadly speaking the term ‘metabolism’ refers to the complex set of mutually regulated and coordinated reactions that take place within every living cell and which enable it to carry out life’s processes. In the context of the origin of life question, ‘metabolism first’ mechanisms presume that some relatively simple autocatalytic chemical cycle, a forerunner of the complex metabolic cycles found in extant life, emerged prior to the appearance of an oligomer-based genomic system. As Stuart Kauffman, the influential theoretical biologist pointed out already in the 1980s, if within a set of molecules or molecular aggregates, say, A, B, C, D, and E, if A catalyses the formation of B, B catalyses that of C, C that of D, D that of E, and finally E that of A, then the closure of that cycle results in the entire cycle become autocatalytic, meaning that the system as a whole is self-replicating.42 The ‘replication first’ school also views life as having been initiated by the emergence of an autocatalytic system, but in this case one based on a template-like oligomeric replicator, such as RNA (or RNA-like). Once such a replicator emerged it is then presumed to have evolved and complexified, eventually leading to the establishment of some simple life form. So the ‘metabolism first—replication first’ debate may also be expressed as which came first, the spontaneous formation of a holistically autocatalytic chemical cycle, or the emergence of some template molecular replicator?
Freeman Dyson, an American physicist, was the first to ask this question directly, and assumed that metabolic complexification and template replication are not logically connected. Dyson proposed that the origin of life involved the independent formation of two separate entities, one genomic, the other metabolic, which then combined to form a system that could be classified as alive, a system both genomic and metabolic.43 That suggestion is actually quite arbitrary and, given the considerable scepticism with which the spontaneous emergence of either of those characteristics has subsequently been viewed, the likelihood of both characteristics emerging spontaneously and independently now seems highly unlikely. Consequently, the debate over the past decades has focused on the question (reductionist in its approach) as to which of these two special characteristics emerged first, molecular replication by a template mechanism, or holistic autocatalysis associated with a chemical cycle already exhibiting some level of complexity? Does the essence of life derive from the sequential nature of certain oligomeric molecules, or from the complexity associated with holistic autocatalysis? The fact that two schools of thought have emerged testifies most eloquently to the fact that neither school is compelling, each having its inherent weaknesses. The fact that the question is asked at all demonstrates too well how rudimentary our understanding of life continues to be. Let us begin by assessing the ‘replication first’ scenario in some detail and see why, despite its status as the basis for the widely-held RNA-world viewpoint, some fundamental difficulties remain unresolved.
‘Replication first’ scenario
As noted above, the ‘replication first’ scenario for the origin of life rests on the idea that life originated with the emergence of some oligomeric self-replicating entity and that replicating entity then proceeded to mutate and complexify until it became transformed into some minimal life form. Historically that idea can be traced back as far as 1914, to an American physicist, Leonard Troland, but that scenario was given a major boost through the contributions of Sol Spiegelman in the late 1960s that we described earlier. Within a short period of time those ideas were given further support through the pioneering works of Manfred Eigen and Peter Schuster in the 1970s.44 Central to ‘replication first’ thinking was the proposal of an RNA-world that preceded the interdependent world of nucleic acids and proteins which forms the basis of all modern life.45 A key attraction of the RNA-world scenario was that it appeared to solve the long-standing ‘chicken and egg’ dilemma with respect to the dual world of nucleic acid and protein. All modern life forms depend critically on this interdependence. DNA, the nucleic acid in which all heritable information is coded, cannot replicate without the elaborate involvement of protein enzymes, and those protein enzymes cannot be generated without the prior existence of the DNA molecule, which codes for those enzymes. So how could this dual world have come about? The RNA-world hypothesis appears to resolve this dilemma through its proposal that RNA originally functioned as both the carrier of genetic information and the provider of enzymatic activity. The fact that RNA can carry genetic information is not surprising. It is, after all, a nucleic acid closely related to DNA. But the discovery by two American researchers, Thomas Cech at the University of Colorado and Sidney Altman of Yale University, that RNA can also act as an enzyme and catalyse key biochemical reactions, gave the RNA-world viewpoint a major boost (as well as a Nobel prize to Cech and Altman). But the RNA-world view critically depends on the idea that a self-replicating molecule could have emerged spontaneously on the prebiotic earth, and that idea has continued to meet with opposition.
A central criticism of the ‘replication first’ scenario is based on the view that conditions on the prebiotic earth were not consistent with the spontaneous emergence of a molecule possessing a self-replicating capability. However, as discussed earlier, this view has no sound basis. The term ‘prebiotic conditions’, so frequently quoted in the origin of life literature, may convey some general information, but is totally devoid of specific information and so cannot be used to rule out any process, if that process is consistent with the basic rules of chemistry. Replicating molecules can be synthesized in the lab, so their spontaneous appearance on the prebiotic earth cannot just be dismissed ad hoc. Our ignorance regarding the prebiotic earth means that we cannot rule out the possibility that such an entity did in fact emerge on the prebiotic earth.
A more fundamental problem with the ‘replication first’ scenario is its apparent incompatibility with the Second Law of Thermodynamics. Let us recall what the ‘replication first’ scenario actually proposes. It rests on the idea that once some self-replicating entity happened to emerge, it then proceeded to complexify until it became transformed into some minimal life form. The difficulty with that proposal is that the simplest living system is a highly organized far-from-equilibrium system, which needs to constantly consume energy in order to maintain that far-from-equilibrium state. In other words for a replicating molecule to have complexified into a simple living system would have meant that instead of reacting to yield thermodynamically more stable products, it ended up becoming a highly complex thermodynamically unstable system. But that’s not how chemical processes proceed. It’s almost as if in a thermodynamic sense the reaction proceeded uphill, whereas, as we have seen, chemical reactions only proceed downhill.
So even if a replicating molecule were to emerge spontaneously, and even if it were to find itself in conditions that enabled the replication reaction to proceed, that reaction would only proceed until it reached the lowest free energy state, the equilibrium state. Once the system reached that low-energy state the process of evolution toward some minimal life form would cease. Indeed four decades of experimentation with replicating molecules has provided no indication of an inclination for such molecules to complexify toward far-from-equilibrium metabolic systems. For the ‘replication first’ scenario to be viable an explanation needs to be offered as to how a simple replicating system would be induced to complexify and ‘climb uphill’. I will say more on this point subsequently. Let us now see how the alternative ‘metabolism first’ school of thought holds up to inspection.
‘Metabolism first’ scenario
A number of distinctly different mechanistic scenarios for the origin of life can be categorized as ‘metabolism first’ and we will not go into their details. The key point is that despite major differences in the essence of their chemistry, all contend that holistic autocatalysis (a catalytic cycle that achieves closure)—in what might be thought of as a primitive metabolism—p
receded the subsequent incorporation of a genetic capability. Second, all presume that the organization required to generate metabolic function came about spontaneously, or through random drift. In other words the ‘metabolism first’ scenarios presume that the functional coherence inherent in metabolic processes can come about of its own accord, that disorganized systems underwent spontaneous organization. But, as has been pointed out by several leading origin of life researchers, in particular Shneior Lifson46 and Leslie Orgel,47 that idea is highly problematic. It’s the Second Law problem again. How would metabolic cycles form spontaneously from simple molecular entities, and, more importantly, how would they maintain themselves over time? We run yet again into that thermodynamic brick wall. The same problem that puzzled physicists with respect to the emergence of cellular complexity is applicable to the emergence of metabolic complexity. Highly organized far-from-equilibrium chemical systems are not expected to be generated by spontaneous ‘downhill’ processes. And for those who say such transformations can take place, despite the Second Law, some experimental demonstration of such an occurrence is necessary. Harry Truman famously said: ‘I’m from Missouri—show me.’ So far no one has.
So both the ‘metabolism first’ and ‘replication first’ scenarios for the origin of life are problematic, not due to some minor issue, but because both have fundamental difficulties with the Second Law. We need to come up with a mechanism for the process of complexification toward a far-from-equilibrium system that does not contravene the Second Law. If, and when, that issue is resolved, the question of ‘metabolism first’ or ‘replication first’ may actually take on a different perspective. The answer to the question as to which came first may then become apparent, or, at the very least, may become less relevant. We will consider a possible resolution of this sticky problem in chapter 7.
Chance or necessity?
The prevailing view that life emerged from non-life leads to an immediate and highly problematic dilemma: was life’s emergence on earth deterministic or was it contingent? In other words, was it a fantastically improbable accident—a freak occurrence that would almost certainly never be repeated—or was life’s emergence inevitable given the existing laws of physics and chemistry. Two Nobel prize-winning biologists have famously faced off on this question. Jacques Monod viewed it as a bizarre accident unlikely to be repeated.10 In his words: ‘That would mean that its a priori probability was virtually zero… The universe was not pregnant with life nor the biosphere with man.’ Christian de Duve, however, takes the opposite view and considers the emergence of life on earth-like planets a ‘cosmic imperative’ governed by the laws of chemistry and physics.48 De Duve goes as far as to contradict Monod with the statement: ‘It is self-evident that the universe was pregnant with life and the biosphere with man. Otherwise, we would not be here.’ So who is right? Did life on earth emerge by chance or necessity (to paraphrase the title of Jacques Monod’s classic text)?
The first point to note is that the Monod and de Duve positions are actually extreme ends of a continuous spectrum of possibilities. To illustrate this point consider the probability of snowfall during winter. Is snowfall in winter deterministic or contingent? In the Swiss Alps snowfall during winter would be considered deterministic. Due to the low temperatures that prevail in the Alps in winter the probability of snowfall is extremely high. Pretty well guaranteed. But on a Queensland beach the probability of snow falling, even in winter, is very close to zero. Queensland temperatures don’t get low enough. What about snowfall in Rome? Here the probability is intermediate—it does snow in Rome on occasion. In the last thirty years it snowed in 2012, 2005, and in 1986. Snowfall in Rome is a contingent event. The conclusion? A particular event could in principle be highly contingent or effectively deterministic or anywhere in between.
Of course one doesn’t have to understand the physics of snowing to be able to state whether snowfall at a particular location is deterministic or contingent. Simply by checking the historical record regarding snowfall at that location, you will have the answer. That’s why we can be supremely confident it will snow in the Alps this winter and that it won’t snow on the beach in Queensland. Regarding Rome, we must remain uncertain. All one can say definitively is that it may snow next winter in Rome, the probability being something like 10 per cent.
So, what can we conclude regarding the emergence of life on our planet? The short answer: almost nothing, and there are several reasons for that frustrating state of ignorance. In contrast to the meteorological phenomenon of snowfall which is well understood, we don’t understand the process by which life emerged, and we are relatively ignorant regarding the prevailing conditions at the time. How can one expect to be able to judge the likelihood of a process we don’t understand and which took place under unknown conditions? Alternatively, as in the case of snowfall, one might be able to make a prediction without understanding the process, simply by carrying out a historical survey of the phenomenon in question. But here we run into a different problem. Our survey is restricted to a sample of one. Even though we are aware that the number of earth-like planets in the universe is likely to be spectacularly large, we only know the life situation on one of these—our own. With a sample of just one to guide us, our ability to reach a reasoned assessment of its likelihood elsewhere in the universe is obviously limited.
6
Biology’s Crisis of Identity
The difficulties in relating living and non-living entities, first with respect to the very strange characteristics of living things (chapter 1) and then with regard to the seemingly intractable origin of life problem (chapter 5) have exposed the scientific quandary that modern biology has been contending with in recent years. In fact three core questions at the heart of the subject—what is life, how did it emerge, and how would one make it—remain troublingly unresolved. And though these questions may initially seem independent and quite unrelated, they are in fact intimately interconnected, as schematically illustrated in Fig. 5. If you think about it, being able to answer any one of the questions depends on knowing the answers to the other two. We don’t know how to go about making life because we don’t really know what life is, and we don’t know what life is, because we don’t understand the principles that led to its emergence. So, despite those spectacular advances in molecular biology over the past sixty years, the very essence of what biology claims to study remains troublingly obscure. That gloomy view is not just the frivolous opinion of an over-zealous chemist on a subject that is not his own, but one that is beginning to be expressed more generally. Carl Woese, in an almost messianic article that we have already referred to, recently wrote:1
Fig. 5. Three key questions governing holistic understanding in biology
Biology today is no more fully understood in principle than physics was a century or so ago. In both cases the guiding vision has (or had) reached its end, and in both, a new, deeper, more invigorating representation of reality is (or was) called for… Look back a hundred years. Didn’t a similar sense of a science coming to completion pervade physics at the 19th century’s end—the big problems were all solved; from here on out it was just a matter of working out the details? Déjà vu!
Woese, a leading contributor to the molecular approach to biology whose fruits have been so rewarding, seems to have lost all faith in the methodology that served him and molecular biology so well. Paradoxically it is the dramatic increase in knowledge brought about by molecular biology that has actually revealed how ignorant we are. So what went wrong?
The road from Darwin to modern biology was a convoluted one. Darwin’s monumental achievement was, of course, in providing biology with a physical foundation, thereby successfully transplanting biology from the supernatural world into the natural world. In doing so, Darwin irrevocably changed our perception of ourselves and the world in which we live. But it was far from smooth sailing. First, natural selection, the very heart of Darwinism, was not fully accepted by biologists till well into the twentieth cen
tury. It was almost eighty years after the publication of Origin of Species, in the 1930s, that Darwinian theory was finally embraced, as part of what is termed the modern evolutionary synthesis. It was the winning integration of Darwinian evolutionary theory with Mendelian and population genetics that finally eliminated academic doubts as to the significance of the Darwinian legacy. That integration provided the mechanism by which natural selection could perform its magic, thereby eliminating the main sources of prevailing criticism.
But another revolution was beginning to build up momentum—the revolution in molecular biology. Indeed as already noted, a half-century of dramatic discoveries beginning with the structural elucidation of DNA in 1953 were revealed in quick succession—DNA replication, RNA transcription, protein translation, the ribosomal machine, with a long string of Nobel prizes illuminating the path to what Walter Gilbert termed the Holy Grail—elucidating the entire base sequence of the 3 billion bases in human DNA, the human genome project in which the entire human genome was sequenced. The reductionist dream appeared to have been realized, the essence of humankind had been reduced to a string of 3 billion letters. On its completion in 2000, Bill Clinton in a White House ceremony dramatically claimed ‘today we are learning the language in which God created life’ and added that the achievement would ‘revolutionize the diagnosis, prevention and treatment of most, if not all human diseases’. Personalized medicine was promised by 2010. Abravenew world was with us, the mysteries of biology were finally solved. Any lingering details still to be resolved were just that—details, hardly worth mentioning in the big scheme of things. Just the way physics felt at the end of the nineteenth century…