by Pross, Addy
Well, at the time of writing, the so-called Holy Grail and the language of life that it was supposed to have taught us have not delivered the promised rewards. Not only hasn’t early twenty-first-century biology reached its goal of solving the major biological problems, but there is a growing awareness that there is a largish elephant in the room. Life is more complicated than a representation provided by a string of 3 billion letters. The gap between the elucidation of the human genome sequence and understanding the significance of that sequence is cavernous. The uncovering of more and more structural and mechanistic information within the living cell hasn’t clarified what life actually is. Stuart Kauffman42 put it in succinctly in his thought-provoking text Investigations:
despite the fine work… in the past three decades of molecular biology, the core of life itself remains shrouded from view. We know chunks of molecular machinery, metabolic pathways, means of membrane biosynthesis—we know many of the parts and many of the processes. But what makes a cell alive is still not clear to us. The center is still mysterious.
What both Kauffman and Woese were effectively saying, each in their own words, was: we see so many trees, yet we have no real view of the forest.
So where’s the problem? The answer in a nutshell is complexity, the organizational complexity that is life. The reductionist strategy for dealing with complexity seems to have floundered. It works great for clocks, it has been a boon for our understanding of the natural world, but its performance in the life arena has been mixed. The spectacular advances in molecular biology, reductionist in its approach, have not opened the gates to the Promised Land. Our attempts to view biological systems as mechanical-materialistic machines have failed dismally. The reductionist methodology has not as yet brought us any closer to answering the basic life questions depicted in Fig. 5, nor the global ones that we discussed in detail in chapter 1. Tibor Ganti, a Hungarian chemical engineer, recognized the problem over thirty-five years ago when he stated that ‘living systems have special properties which arise primarily not from the substances of the system, but from their special organizational manner.’49 It is the organization of life rather than the stuff of life that makes life the unique phenomenon that it is.
So how do we deal with that troublesome issue of organization—the very special kind of organization associated with all living things. Over recent decades, scientists of various kinds—physicists, chemists, mathematicians, and not just biologists, have been exploring alternative approaches to the problem. One direction taken was to argue that physics and biology were necessarily based on different philosophies of science and, therefore, that biology should be recognized and treated as such. For fundamental but unspecified reasons, biology was viewed as not being reducible to physics, even though reduction had proven so successful in bridging between physics and chemistry and making sense of the inanimate world. Divide and conquer! Indeed, that way of thinking seems to have bolstered the holistic approach to biology, as expressed by the burgeoning area of systems biology. Let me briefly describe that approach, both its benefits and its apparent shortcomings.
In contrast to molecular biology, in which the focus is on the structure and reactivity of individual molecules and molecular aggregates within the cell, systems biology attempts to address the manner in which these cellular components interact as a system. After all it is the system as a whole, not just individual components, that is responsible for biological function. Inherent in the systems approach is the belief that there are general features of systems, in particular their network topology, which characterize the system’s behaviour, and that such understanding may provide biological insights.
But the systems biology approach has not proved a nirvana. General rules governing the behaviour of complex systems have not as yet been delineated and in any case it is clear that without sufficient attention to component functionality, the systems insight will on its own be necessarily limited. As we discussed in chapter 3, the terms reduction and holism do not have to be mutually exclusive, so that in many respects the holistic approach can be thought of as reductionism dressed up. Given this inconclusive and rather unsatisfying situation, systems biology has routinely resorted to falling back on the concept of ‘emergent properties’ whenever the system’s properties are not readily explained through a reductionist approach. But the use of that catchphrase is a double-edged sword. Sweeping unexplained phenomena under the expansive complexity carpet creates the illusion of explanation, which, in itself, can be problematic. A phenomenon that is unexplained will continue to attract attention until some convincing explanation is offered. But once some unexplained phenomenon is classified as an ‘emergent property’, it could be thought of as explained, that no further consideration of the phenomenon is required. How else to understand the almost total lack of interest that the scientific community has shown in the physicochemical basis for teleonomy, that most remarkable of emergent properties? Jacques Monod in his classic Chance and Necessity considered the problem of teleonomy as the ‘central problem of biology’.10 As Monod put it: how could purposeful systems have emerged from a universe with no purpose? But the minimal attention that has been directed toward this ‘central problem’ suggests that the scientific community considers the problem solved (or uninteresting) and has accepted the ‘emergent property’ explanation.
Another reason that the biological community might have ignored Monod’s challenge is that his question might sound more philosophic than scientific. But don’t be fooled. The question of how purpose and function can manifest themselves spontaneously is a profoundly important scientific question and its resolution would help connect chemistry, representing the objective material world, with biology, representing the teleonomic world. Bottom line: Darwinism did bring about a sense of unity within biology, but the troubling consequence of that unification, of enormous value in itself, has been a growing isolation of the subject from the physical sciences to which it must necessarily connect.
Let us now briefly consider two other approaches that have been taken in the past several decades to try to crack the complexity nut—one physical, the other mathematical, and review their current status. The physical approach to the problem came about through the observation of physical systems, such as hurricanes, whirlpools, vortices, and the like. The theory of such systems, attributed primarily to work of the Belgian physical chemist Ilya Prigogine in the 1950s and 1960s is covered by what is termed non-equilibrium thermodynamics50—a mouthful for those who do not work in the area, and I will spare the reader a detailed discussion. The main point worthy of mention is the fact that some connection between certain non-equilibrium physical systems and biological systems is claimed to have been found. Recall that one of the mysteries of biological systems is how their non-equilibrium complexity came about naturally. But fill a bath tub with water, pull out the plug, and from a purely physical point of view something intriguing occurs. Whereas the body of water in the bath is in a stable state when the plug is in place, removing that plug creates an unstable situation as the body of water can reduce its potential energy by flowing down the drain. Of course the body of water immediately responds to this unstable situation—it begins to flow down the drain in order to lower its potential energy and reach a new equilibrium state. But in doing so something special takes place—the body of water generates a structure, a vortex. The non-equilibrium state has spontaneously generated a non-equilibrium structure. The body of water that initially lacked any structure has in some sense acquired order. In the language of non-equilibrium thermodynamics that structural pattern, which is evidenced in other physical systems as well, is termed a dissipative structure.
This physical pattern has led to the idea that in purely energetic terms some similarity exists between dissipative structures and living cells. Both are non-equilibrium, meaning they are unstable, and both have generated a non-equilibrium structure which must continually consume energy to maintain itself (in the case of the bath the source of ener
gy is the lowering of the water’s potential energy as it flows out of the bath). In other words the claim is made that one of the mysteries of life may have a simple physical resolution. Organization can be induced in an open system that consumes energy. The far-from-equilibrium organization of a living cell may in some sense be thought of as mimicking the non-equilibrium order induced in a tub of water or a heated column of liquid. The mystery of biological organization may have been at least partly resolved. These ideas were discussed with some enthusiasm some 20–30 years ago and without going into further detail, the approach seems to have lost much of its earlier appeal. The main difficulty is that the disarmingly simplistic connection between the physical and biological systems mentioned above did not lead to any useful biological insights. A model is only useful if it provides new insights and makes novel predictions. However, as was noted some years ago by John Collier, a philosopher at the University of Calgary, there is no evidence that the laws of non-equilibrium thermodynamics apply to biological systems in a non-trivial fashion.51 Non-equilibrium thermodynamics has not proved to be the hoped-for breakthrough in seeking greater understanding of biological complexity. A physically based theory of life continues to elude us.
Enter the mathematical approach to complexity. In 1970, the Princeton mathematician John Conway invented a game which he called Life, which leads to interesting insights.52 The game is based on a two-dimensional square grid where each square can exist in one of two states, dead or alive, most simply represented by the squares being black (alive) or white (dead). One starts the game with some particular limited pattern of live squares and then based on a rule that is specified, all eight squares surrounding each square (neighbours) are then made black or white, depending on the particular rule chosen. For example, the rule may be that any live cell with fewer than two live neighbours dies (it becomes white), any live cell with two or three live neighbours stays alive (stays black), any live cell with more than three live neighbours dies (becomes white), and any dead cell with exactly three live neighbours becomes a live cell. The process then is repeated many times to see how the initial pattern evolves over time. Depending on the starting pattern and the rule of the game, very different patterns can emerge. Sometimes the pattern remains unchanged (for example if the above rules are applied to a starting pattern of a 2 × 2 square block of live squares), sometimes it simply disappears after a few runs, but sometimes, quite extraordinarily complex patterns result. The game of Life teaches us that simple rules can lead to quite complex patterns and while the rules specified in the game of Life have no relevance to real life, the fact that complex systems may result from the operation of relatively simple rules is informative in itself. In fact we will demonstrate in the next chapter that real life does indeed appear to be governed by a simple rule, though we will need to discuss the nature of simple replicating systems before that rule can be appreciated. While Conway’s Life game has opened up interesting insights into complex systems in general, direct insights into the nature of living systems do not appear to have been forthcoming.
Let us sum up the key conclusions from the above discussion. We have already noted that the problem of ‘understanding life’ involves more than merely accumulating further molecular insights into life’s mechanisms. As the younger generation might say: been there, done that. We need to be able to explain life’s complexity and the global characteristics associated with that complexity, and we are far from being able to do that. The non-equilibrium thermodynamic approach discussed above, though interesting in its own right, appears to have led to a dead-end. With regard to the attempts of biologists to better understand life’s complexity through the newly emergent area of systems biology, the jury is still out. But current indications are that no major breakthroughs are imminent. While a systems biology approach may provide insights into specific biological problems, there is no indication that the approach is able to resolve the larger questions that have been raised. And though the mathematical approach to complexity has been instructive in offering new insights into complexity in general, it does not appear to have contributed in any significant way to untangling the tangled web that is particular to biological complexity. So how to proceed? In the final two chapters we will attempt to show how recent fascinating results within a newly founded and burgeoning area of chemistry can finally provide some concrete answers.
7
Biology is Chemistry
Systems chemistry to the rescue
Our earlier discussion has identified the nature of biological complexity as the nut that needs to be cracked. So, in addressing this problem, has reduction, that tested scientific methodology that stood us in such good stead these past several hundred years, reached its effective limits? Is a new methodological approach needed? A range of prominent biologists have been arguing in the affirmative. However, my answer remains no. In this chapter, I will describe the basis of that view, and attempt to demonstrate that there is a way forward, that the reductionist approach can be effectively applied to biology at the global holistic level. I will attempt to show that the chasm separating biology and chemistry is bridgeable, that Darwinian theory can be integrated into a more general chemical theory of matter, and that biology is just chemistry, or to be more precise, a sub-branch of chemistry—replicative chemistry. Despite the widespread concerns that have been raised with regard to the reductionist methodology in biology, the organizational issue can be resolved through a reductionist analysis.
In chapter 4, I mentioned that a relatively new area of chemistry, systems chemistry, has taken shape in recent years. This new field came about in trying to seek out the chemical origins of biological organization, and that explains its name, a play on words with its better-known cousin, systems biology. If we think of biology as the field of endeavour that studies those highly complex chemical systems capable of replication or reproduction, then systems chemistry (or at least central aspects of it) deals with relatively simple chemical systems that also possess that special characteristic of self-replication, and in doing so attempts to fill the chasm-like void that continues to separate chemistry and biology. In contrast to systems biology, which takes a ‘top-down’ approach in its attempt to contend with life’s complexity, systems chemistry takes a ‘bottom-up’ approach. A top-down approach starts with what we have and works down from there seeking to understand the manner in which the components contribute to the whole. A bottom-up approach, needless to say, goes the other way—it starts from some presumed beginning and works its way up. In the life context that means that life’s complexity is addressed by investigating the manner in which complexity was built up, step by step, from some initial simple entity, from the bottom up. A key challenge of systems chemistry then becomes to ascertain the rules, if such rules exist, which govern that process of complexification from a relatively simple chemical system to the highly complex systems that define present-day biology.
There are a number of factors that argue favourably for the bottom-up approach. First, we have already noted that life is presumed to have had its beginnings in inanimate matter, i.e., life emerged from non-life. That being the case it necessarily follows that life’s beginnings were simple and that its complexity was built up over an extended time period, step by step. That, in itself, confers on the bottom-up approach a crucial advantage. The path leading from bottom to top is not merely conceptual—a gedanken experiment—but an actual pathway that was followed by a real chemical system. It now seems increasingly likely that several billion years ago some replicating system of unknown identity, but of low complexity, set off along the long and winding road toward high complexity, and that historic path of ever-increasing complexity eventually led from the world of chemistry to the world of biology. The fact that a reasonably well-defined process of complexification can be identified suggests that there may well be a driving force for that process, and one of our goals will be to seek its identity and explore its nature. Can that process of complexification be under
stood in physical terms?
Second, it seems logical to suggest that if life did start off simple, then life’s fundamental nature would become more understandable by examining earlier, and therefore simpler prototypes. An analogy may make this clear. If we want to understand what an airplane is, as well as the underlying principles that enable these modern behemoths to take to the air, then examining a fully equipped Boeing 747 will not be the most productive way to proceed. A Boeing 747 is an immensely complicated entity composed of some 6 million individual parts and over 200 kilometres of wiring, so figuring out the relevance of each and every part to the whole, and uncovering the basis for its flying capability, would be overwhelmingly difficult. Some of those parts, for example, passenger TV screens, steward call buttons, ovens for heating food, etc., wouldn’t be particularly relevant to its flying capability. So where is one to begin? If you want to figure out what an airplane is, and the principles governing its flight, you’d be much better off examining an earlier simpler airplane, say the Wright brothers’ 1903 prototype or some other simple equivalent, where the number of components is a tiny fraction of that in the Boeing, and one in which every component plays an important, if not critical role in enabling that entity to become airborne. And that’s where systems chemistry comes in—by examining the workings of simple replicating systems and the networks they generate, we are attempting to do the equivalent of examining the Wright brothers’ airplane rather than a Boeing 747.
Of course the bottom-up approach toward resolving the life issue assumes that life did start off from simple beginnings and that a process of complexification from that simple beginning did take place. As discussed in chapter 5, that is the generally accepted view. It is the nature of that process that continues to be a source of intense debate, rather than whether the process took place. But, as we will shortly see, the emergent area of systems chemistry will also provide additional empirical support for that assumption. The goal of this chapter is therefore ambitious: to demonstrate that the study of systems chemistry can lead to the smooth merging of living and non-living systems, thereby offering a unifying framework for chemistry and biology. Such unification would be of considerable value as it would place biology within a broader chemical context. Indeed, if successful, that endeavour could provide fundamental insight into the ‘what is life’ question as it could offer a description of living systems in chemical rather than biological terms. So despite recent misgivings regarding the reductionist methodology as applied to biological systems, we will attempt to show that reduction in biology is alive and kicking (no pun intended!). In addition, a not insignificant side benefit would be to demonstrate that systems chemistry can throw light on the origin of life problem, at least in an ahistorical sense, by uncovering the principles that would have enabled inanimate matter to complexify in the biological direction toward life.