What is Life?:How chemistry becomes biology (14 page)

Consider, you establish a group of leading biochemists, synthetic chemists, molecular biologists, and you ask them to create a simple living system in their laboratory. No restrictions of any kind, no chemical limitations, none of the constraints that would have necessarily accompanied conditions on the prebiotic earth. And no funding limitations either! Offer them whatever materials they would like in any combination they would like—DNA and RNA
oligomers, lipids, assorted proteins, sugars, any catalyst they would want, and, of course, any instrumentation they might require. Create for them any reaction conditions needed to carry out their experiments, prebiotic or otherwise. If they request simulated conditions resembling those within a hydrothermal vent, no problem. Clay surfaces? That one’s easy. But the honest response? Most would not really know where to start!

Certainly, a number of audacious scientists, such as Jack Szostak, the Nobel geneticist at the Harvard Medical School, and Pier Luigi Luisi, the venerable Italian chemist, have taken some tentative steps toward that ambitious goal,
⁴¹
but for reasons we will discuss in
chapter 8
, the obstacles in reaching the target remain formidable. The problem of how life emerged on the prebiotic earth is not just about what materials were available and identifying the reaction conditions at the time, because even the very best chemists without any resource limitations would not really be sure how to proceed. And the problem does not stem from the fact that one particular step or other in the recipe for life is especially difficult and still technically out of reach. The problem is more fundamental. The problem is there is still no coherent recipe. As we noted earlier, we don’t yet adequately understand what life is, so how can one go about making something that we do not as yet fully understand? So, in a fundamental sense, the efforts to uncover prebiotic-type chemistry, while of considerable interest in their own right, were never likely, in themselves, to lead us to the ultimate goal—understanding how life on earth emerged.

In fact we would go so far as to say that seeking historical information regarding the emergence of life on earth is a honey trap—seductively appealing, beckoning both the novice and the experienced
researcher, but one that is unlikely to yield genuine insights with respect to the question it poses. More significantly however, historical evidence alone, even if it were to become available, would not resolve the problem. The real challenge is to decipher the ahistorical principles behind the emergence of life, i.e., to understand why matter of any kind would tend to complexify in the biological direction. It is this ahistorical question, independent of time and place, which lies at the heart of the origin of life problem. In order to resolve the origin of life mystery, and it is a mystery, we need an understanding of the physicochemical processes that would have converted inanimate matter of whatever kind into a chemical system that we would categorize as living.
That
is the issue that kept the great twentieth-century physicists awake at night, not prevailing uncertainties with regard to the composition of the prebiotic atmosphere or the feasibility of synthesizing nucleotides under prebiotic conditions, and the like. What laws of physics and chemistry could explain the emergence of highly complex, dynamic, teleonomic, and far-from-equilibrium chemical systems that we term life?

Of course, once the general principles that govern such transformations have been characterized, there is still no guarantee that the historical question can then be resolved. After all, we are talking about particular events that took place on the earth some 4 billion years ago, so our ability to uncover the nature of those historical events is limited in the extreme. However, if and when that ahistorical question
is
resolved, the problem of how life on earth emerged on the prebiotic earth would take on a totally different aspect. Being a historical question the answer might remain unknown, but the issue would no longer be a mystery in the same way that it is now. Importantly, based on the above discussion, I am of the view that
attempting to seek out life’s molecular beginnings
before
we have adequately clarified the physicochemical principles that underlie biological complexification is tantamount to attempting to assemble a watch from its component parts—springs, cogs, wheels, etc.—without understanding the principles that govern watch function. Richard Feynman, the iconic Nobel physicist, once said: ‘What I cannot create, I do not understand.’ This truism might be usefully turned around: What I do not understand, I cannot create.

I have described in some detail the limitations in tackling the origin of life problem through its historical aspect, so let us now consider how the problem may be tackled through its ahistorical aspect. And it is here that we’ll find room for greater optimism. Ahistorical principles are as relevant today as they were 4 billion years ago—the rules of physics and chemistry do not change over time. So rather than speculate as to what
might
have transpired on the prebiotic earth, let us investigate what
does
take place on today’s earth. Let us study and experiment with chemical systems of the right kind, in order to glean information and obtain insight into this key question.

As we mentioned in
chapter 4
, systems chemistry deals with the class of simple replicating molecules and the networks that they create. That area of study, still in its infancy, has already revealed that reactivity patterns observed in such systems are quite different from those we find in ‘regular’ chemistry, and may provide insight into the kind of chemical processes that led to the emergence of life. In fact the switch in emphasis from historical to ahistorical leads us directly to an issue that has been central to the origin of life debate for several decades. Since all living systems are characterized by possessing a metabolism and the ability to reproduce themselves,
which of these two capabilities came first—replication or metabolism? At first the question might sound historical in its approach—which came first? But the nature of these two capabilities may be such that chemical logic could dictate the natural order to be expected, and, as a consequence, could provide insight into the process of emergence. As we will see, the implications of the ‘metabolism first—replication first’ dichotomy are significant because they directly impact on all three questions that make up the triangle of holistic understanding, namely, what is life, how did it emerge, and how would one make it.

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.

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.