 |
Web Hosting by Netfirms | Free Domain Names by Netfirms |
|
|
|
From Section 1: Essential Cancer
As we head into new territory it might be a good idea to make sure we are certain of the ground we have already covered. The standard approach to doing this would be to summarize the material presented so far, but as I said in the introduction this the account of a journey not a textbook, so instead I want to begin by retracing one the main themes of our exploration so far. Fittingly, it concerns the Earth's original inhabitants and the creators of the living world as we know it: the cells.
As with all living things, the survival of cells - be they free-living organisms like bacteria and protists or the components of complex organisms like us - involves a wide range of dynamic interactions; for instance simple experiments can demonstrate that the basic components of cells are continually turning over as raw materials, energy and biomolecular information flow between them and their surroundings. The dynamism of cells is also reflected by more obvious changes in their physical make-up and behaviour. These changes range from superficial and transient alterations such as the extension of pseudopods by amoebas to engulf morsels of food, to radical, permanent and heritable transformations that affect fundamental aspects of cellular life. For example as hematopoietic cells proceed along the evolutionary journeys that we recognize as differentiation pathways they undergo changes that have profound consequences for their structure, behaviour, gene expression patterns and survival.
The responses, adaptations and developmental changes of cells can be shaped by a wide range of influences, which can act in many different ways (e.g. internally, externally) to produce a wide range of effects (e.g. immediate and cumulative) and combinations (e.g. additive, synergistic), and this dynamic complexity means that the experiences of all cells, lineages and populations are subject to contingency and chance, hence each evolutionary journey is ultimately unique. This does not mean that cellular evolution is unpredictable. For example a quartet of mammalian embryos may look virtually identical in the earliest stages of development, but once we know certain facts about their hereditary backgrounds and the conditions under which they are developing we can safely predict that one pair of embryos will give rise to mice in a few weeks while the others will develop into elephants over several months. We can also expect chance factors to ensure that even when embryos are derived from the same fertilized egg and develop in the same environment they will diverge from each other to some extent as they develop; for example identical twins will have different fingerprints and blood vessel patterns.
A mouse is obviously different from an elephant, but both are the products of similar patterns of cellular evolution: in each case a zygote gives rise to a population of cells whose members rapidly differentiate into distinct subpopulations and lineages, each of which passes through a predictable and often radical sequence of changes as it contributes to the assembly, maintenance and survival of a complex self-regenerating living organization. We observe similar patterns unfolding during the development and regeneration of most multicellular organisms, but this is certainly not the only pattern of cellular evolution we can recognize in the living world; in fact it is relatively novel in a biosphere where unicellular organisms constitute a long-established majority. The evolution of free-living cells features changes that are relatively rare, modest, unpredictable and uncoordinated when compared to their complex cousins, and their dominant context of survival and change appears to be more competitive than co-operative. For instance recent times have witnessed the sudden rise to prominence of several lineages of human and animal parasites which share the critical competitive advantage of being resistant to treatments that were once broadly effective against them; for example many disease bacteria are now resistant to antibiotics.
An interesting thing about antibiotic-resistant bacteria is that the key factor which determines whether cells are resistant or sensitive to a particular drug is often a single gene. This can be proven experimentally by using modern technology to transfer pieces of DNA containing resistance genes between cells, and the natural ability of bacteria to perform similar transfers on their own has allowed some lineages to accumulate collections of such genes, making them immune to several drugs simultaneously. These multidrug-resistant strains highlight the fact that not only do the evolutionary journeys of the two main classes of cells in the living world show striking differences in their overall patterns of change, they also differ in the kinds of changes they feature. Among free-living cells,significant evolutionary changes are typically associated with the appearance of new variations and combinations of genomic information, which can be generated both by sporadic events - such as random encounters between energetic particles and DNA macromolecules - and by adaptations that allow cells to rearrange, exchange and combine their DNA. In contrast, most of the differences that emerge among the cells of multicellular organisms during epigenesis, growth and regeneration are associated with physical alterations, which typically involve specific responses to their surroundings and experiences. For example the differentiation of erythroid regenerating cells in the bone marrow involves turning certain genes on or off in response to chemical signals transmitted by cells in the thyroid and kidneys.
Modes of Cellular Evolution
When we consider cellular evolution from a general perspective - which is to say one that takes into account the kinds of changes cells undergo, the patterns they present and the contexts in which they change - we can recognize some striking differences between the evolution of free-living cells and those that serve as components of complex organisms. In fact we could go so far as to propose that there are two distinct modes of cellular evolution operating within the living world. Since most of the changes that appear among them are physical rather than genomic, and those changes are associated with the co-operative roles cells assume as they evolve, we can describe the primary mode of evolution among the cells of complex organisms as physical-co-operative. Meanwhile out in the biosphere at large, a genomic-competitive mode of evolution appears to prevail among cells that exist as organisms in their own right.
These distinctions are of course not absolute. Most cells are capable of responding to their surroundings and physically adapting to their situations - for instance by changing shape or adjusting the expression of their genes - and such changes can often be passed on to subsequent cellular generations. All cells are also subject to influences that can alter the genomic information they inherited from their ancestors, if for no other reason than that there is a significant likelihood that a new nucleotide base sequence will be created whenever a nucleic acid macromolecule is replicated. As for the distinction between co-operation and competition, few cells live in situations that are exclusively ruled by one context or the other. For instance under some conditions neighbouring cells in the same tissue may be competitors for oxygen or nutrients, while bacteria that are active competitors for such essentials can also become involved in intimate co-operative arrangements like biofilms and symbiotic communities such as stromatolites.
That having been said, there is no denying that we can easily recognize some fundamental differences in the way the living world's two main classes of cells evolve, and this naturally leads us to wonder how and why such differences came to be. This question is much easier asked than answered; indeed in order to address it with any authority we would have to solve two of the greatest mysteries in the history of life on Earth: when, where and how did the first cells appear, and when, where and how did their descendants - after labouring for eons to make our planet the kind of place where such creatures can survive - give rise to multicellular organisms? We do not know and we may never know some of the basic facts required to solve these mysteries - for instance we do not know how many times cells and complex organisms emerged independently - but we can at least establish some basic historical contexts for cellular evolution. For instance for a start we can say that barring the intervention of meddling aliens, every time a unicellular organism divides it extends a cellular lineage that runs all the way back to the dawn of life on Earth. Narrowing our focus, we can also predict that if we could retrace the evolutionary journeys of those lineages we would find that many of the changes which have become established among their representatives have contributed to their success in struggles to survive, compete for resources and contribute to posterity - or in Darwinian terms, the changes have been favoured by natural selection.
Shifting our focus to complex organisms, we may not be able to say much about their initial appearance on the scene but we can say that like their unicellular cousins, each time a cell within a complex organism divides it extends a lineage that goes back to the dawn of life. Narrowing our focus to the histories of individual cells, lineages and populations within individual complex organisms, we find that the vast majority are not directly involved with the perpetuation of organism lineages, and when we trace their development we often find them changing in ways that can have negative consequences for the cells themselves; for instance most somatic cell lineages terminate with cells that commit suicide and/or lose the ability to reproduce. Of course such cells can still make significant contributions to the welfare of the organism that gave rise to them as it struggles to survive, compete for resources and contribute to posterity - a contribution that is associated with the germ cells, which unlike their somatic siblings often develop in ways that enhance their genomic variability. For example in most vertebrates the chromosomes inherited from an individual's parents are rearranged and reassorted during meiosis so that the resulting gametes carry new genomic combinations, which become even more novel when they fuse to form zygotes.
Thus when we look inside our own bodies we see developmental differences between somatic and germ cells that are reminiscent of the evolutionary differences we have noted between free-living cells and those in complex organisms. This observation complicates our general picture of cellular evolution somewhat, but it also brings us to the point where we can start making sense of what we see going on in the living world. For example we can begin to appreciate the basic aspects of another of the living world's great mysteries: epigenesis.
Complexity and Risks
Suppose we were assigned the task of designing a way for lineages and populations of cells to grow and evolve together to produce highly complex, reproducible and self-regenerating structures. Leaving aside the mechanical details, one thing that is immediately obvious is that no matter what kind of organisms we want to end up with our chances of producing consistent, viable and reproducible results will be much better if we base our assembly processes upon predictable changes produced by specific and consistent cellular responses to particular situations, rather than rely upon the unpredictable changes that are produced by random genomic mutations, rearrangements and recombinations. In fact the only thing we can confidently predict about such unpredictable changes is that they have a good chance of disrupting co-operative and/or co-ordinated cellular interactions; for example a mutation in a transcription factor gene may alter the way cells respond to growth signals. Thus ideally we would want to design complex organisms so that the likelihood of unpredictable variations appearing among their cells was kept as low as possible and any changes that did occur were either corrected or compensated for.
Complex organisms and their cells have of course met or exceeded our hypothetical expectations. For example the likelihood of genomic changes appearing among the cells that make up a typical human body are kept extremely low via chromosomal packaging, high-fidelity replication complexes and DNA repair mechanisms, while the potential impacts of any variations that do appear among our cells are limited by genomic redundancy (e.g. if a gene takes a mutational hit, its normal homologue can still provide the necessary product), specialization (most cells express only a small subset of the templates in their genomes) and a generous DNA-to-gene ratio (this may be more an accident than an adaptation, but it still reduces the likelihood of a random DNA change affecting a functioning gene). The existence of these adaptations confirms our suspicion that with few exceptions - such as immune cells - the risks associated with the spontaneous appearance of genomic variations among the somatic cells of complex organisms have over the long run considerably outweighed the potential benefits.
The risk/benefit calculations change considerably for cells that are obliged to participate directly in the struggle to survive, compete for resources and contribute to posterity. The risk side of the equation remains much the same - indeed cells that carry only one copy of each gene (e.g. bacteria) can be more sensitive to genomic changes than our own cells - but as we saw in the example of bacterial antibiotic resistance, genomic novelties can also be quite useful unicellular organisms. Indeed as that example also illustrates, genomic novelties often represent uniquely powerful solutions to survival challenges. For example if we take away antibiotic resistance genes it is hard to imagine any other way for bacterial cells to become instantly, permanently and heritably immune to one drug, let alone several simultaneously. Thus it makes sense that not only have sporadic genomic novelties like point mutations long featured prominently in the evolution of unicellular organisms, many lineages have also come up with ways of actively exchanging genomic information and generating new combinations. For example T. M. Sonneborn showed in a series of classic studies that the humble Paramecium is capable of exchanging information and rearranging its genome in such a dizzying variety of ways that if Mendel had used these protozoa as experimental subjects he probably would have given up long before he made hide nor hair of heredity.
These observations of life in the unicellular world are relevant to complex organisms for two reasons. The first is historical: we can be reasonably certain that cells were experts at exchanging genomic information and generating novelties long before they learned how to build sophisticated multicellular arrangements. The second reason goes back to our hypothetical design problem: if we assume that the ability to generate genomic novelties is generally useful to all competitors in the Darwinian game, then we would certainly want complex organisms to retain this advantage. Thus the ideal design solution would be one that gave complex organisms the best of both worlds where their cellular evolution is concerned, and sure enough when we look inside our own bodies that is essentially the situation we find. The risks of unpredictable changes among somatic cells are kept low via adaptations associated with mitotic cell division, while the likelihood of new genomic combinations appearing in gametes and zygotes is kept high via adaptations associated with sexual reproduction, such as meiosis and chromosome recombination. Like our unicellular cousins we run some risks by deliberately generating genomic variations; for instance a sizeable proportion of human zygotes fail to develop due to gross mutations. Nevertheless, the long-term benefits to lineages and populations appear to have considerably outweighed the short-term risks to individuals.....