Neo-Darwinism, the modern synthesis and selfish genes- are they of use in physiology?

J Physiol 589.5 (2011) pp 1007–1015 1007 TOPICAL REVIEW Neo-Darwinism, the Modern Synthesis and selfish genes: are they of use in physiology? Denis Noble Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK This article argues that the gene-centric interpretations of evolution, and more particularly the selfish gene expression of those interpretations, form barriers to the integration of physiological science with evolutionary theory. A gene-centred approach analyses the relationships between genotypes and phenotypes in terms of differences (change the genotype and observe changes in phenotype). We now know that, most frequently, this does not correctly reveal the relationships The Journal of Physiology because of extensive buffering by robust networks of interactions. By contrast, understanding biological function through physiological analysis requires an integrative approach in which the activity of the proteins and RNAs formed from each DNA template is analysed in networks of interactions. These networks also include components that are not specified by nuclear DNA. Inheritance is not through DNA sequences alone. The selfish gene idea is not useful in the physiological sciences, since selfishness cannot be defined as an intrinsic property of nucleotide sequences independently of gene frequency, i.e. the ‘success’ in the gene pool that is supposed to be attributable to the ‘selfish’ property. It is not a physiologically testable hypothesis. (Received 24 October 2010; accepted after revision 29 November 2010; first published online 6 December 2010) Corresponding author D. Noble: Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK. Email: [email protected] Introduction behaviour and economics. Attributes like ‘selfish’ and ‘cooperative’ have different meanings when applied to Interpreting molecular genetic information in terms of objects or ensembles at different levels. Cooperation at higher level functions in the organism is a major current the level of protein networks, for example, may occur goal in the physiological sciences, as is the reverse even if the organism in which they cooperate is ‘selfish’ strategy of bottom-up reconstruction: they complement at the level of the phenotype, and vice versa. The concept each other. Computational systems biology is one of the of level in evolutionary theory requires careful analysis tools being used (Kohl & Noble, 2009; Hunter et al. 2011). Achieving this goal could also be a route through which physiology can reconnect with developmental and evolutionary biology. I will explain why some central aspects of neo-Darwinism (or the Modern Synthesis – in Denis Noble is Emeritus Professor of this article I am not always distinguishing between them), Cardiovascular Physiology in the and their most popular expression in The Selfish Gene Department of Physiology, Anatomy and (Dawkins, 1976, 2006), form a barrier to the new synthesis Genetics at Oxford University. Fifty years ago he published the first mathematical required between physiology and evolutionary theory. The model of the electrical activity of the heart barrier can be removed by taking an integrative, multilevel based on experimental measurements approach in which genes and many other components of of ion channels. This has since been organisms that are inherited are viewed as co-operating developed into the virtual heart project in networks to express what we call the phenotype (Kohl within the Human Physiome Project of the International Union of Physiological Sciences (IUPS). He is et al. 2010 Fig. 2, reproduced here as Fig. 1 below). In currently the President of IUPS. He is author of The Music of Life this paper, ‘co-operative genes’ carries this sense, which (Oxford University Press, 2006), the first popular book on systems should be clearly distinguished from the idea of genes ‘for’ biology, now translated into seven foreign languages. co-operative behaviour used widely in ecology, animal  C 2011 The Author. Journal compilation  C 2011 The Physiological Society DOI: 10.1113/jphysiol.2010.201384 Downloaded from J Physiol (jp.physoc.org) by guest on October 24, 2013 1008 D. Noble J Physiol 589.5 (Gould, 2002; Okasha, 2006). Concepts and mechanisms 2009; Goldenfeld & Woese, 2011), a process now known do not necessarily carry through from one level to another to extend beyond prokaryotes (Keeling & Palmer, 2008); – an important point to bear in mind also in multi-level and the inheritance of acquired characteristics, commonly physiology. but mistakenly (Noble, 2010b) called ‘Lamarckism’. I start with a clarification of the relationship between For further examples see Pigliucci & Muller (2010a, neo-Darwinism, the Modern Synthesis and the selfish gene particularly their Fig. 1.1; 2010b) and Jablonka & Lamb idea. Neo-Darwinism (a term introduced by the physio- (2005). logist Georges Romanes (1883)) and its development (see In the rest of this article reference to neo-Darwinism Pigliucci & Muller, 2010a for the relevant history) into should be taken to include the Modern Synthesis. The the Modern Synthesis (Huxley, 1942) as a gene-centred selfish gene idea (Dawkins, 1976, 2006) is a popularization view of evolution can of course be stated without of neo-Darwinism which goes beyond it to characterise reference to the selfish gene idea. Neo-Darwinism is genes as elements in organisms with specific (selfish) the term popularly used, even today, for the synthesis behaviour. As we will see later, it was originally formulated between Darwin’s theory of evolution by natural selection as a literal scientific hypothesis. The question of its status and the assumption that the variations on which is a major focus of this paper. selection acts are produced solely or primarily by gene Another way of stating the claims of this article is that mutations, though the term Modern Synthesis is more they are twofold: first, that neo-Darwinism is, at the least, correct since Romanes coined the term neo-Darwinism incomplete as a theory of evolution. Second, that the selfish before Mendel’s work on genetics was rediscovered. The gene idea adds nothing since it is essentially empty. These Modern Synthesis adds discrete (Mendelian) inheritance are separate claims, even though in the minds of many to neo-Darwinism. Alternatives to the Modern Synthesis biologists neo-Darwinism and the selfish gene idea are not include: symbiogenesis, the idea that major steps in always clearly distinguished. Neo-Darwinism is capable evolution, such as the formation of eukaryotes and of falsification. Indeed, in its original form as a complete multicellular organisms, resulted from cooperation and/or theory, it has already been falsified. We now need to admit fusion between different organisms; horizontal gene trans- processes outside its remit, so that it needs to be extended fer within and between organisms (Woese & Goldenfeld, (Woese & Goldenfeld, 2009; Pigliucci & Muller, 2010b). Figure 1. Relations between genes, environment and phenotype characters according to current physio- logical and biochemical understanding This diagram represents the interaction between genes (DNA sequences), environment and phenotype as occurring through biological networks. The causation occurs in both directions between all three influences on the networks. This view is very different from the idea that genes ‘cause’ the phenotype (right hand arrow). This diagram also helps to explain the difference between the original concept of a gene as the cause of a particular phenotype and the modern definition as a DNA sequence. For further description and analysis of the ideas behind this diagram see Kohl et al. (2010) from which the diagram is reproduced. Reprinted by permission from Macmillan Publishers Ltd: Clinical Pharmacology and Therapeutics 88, 25–33;  C 2010 .  C 2011 The Author. Journal compilation  C 2011 The Physiological Society J Physiol 589.5 Neo-Darwinism, the Modern Synthesis and selfish genes 1009 As I will show in this paper, the selfish gene idea is not Is the ‘selfish gene’ story metaphor or empirical even capable of direct empirical falsification; it has to be science or both? judged by different criteria. Genes, as DNA sequences, do not of course form selves in any ordinary sense. The DNA molecule on its own does absolutely nothing since it reacts biochemically The concept of a gene has changed, and is still only to triggering signals. It cannot even initiate its changing, so what version do we use? own transcription or replication. It cannot therefore be A serious problem in assessing the nature and utility characterised as selfish in any plausible sense of the word. of the selfish gene story in physiological research If we extract DNA and put it in a Petri dish with nutrients, it is that the concept of a gene has changed (see will do nothing. The cell from which we extracted it would, Fig. 1) in fundamental ways (Pichot, 1999; Keller, 2000; however, continue to function until it needs to make more Beurton et al. 2008). We are dealing with a moving proteins, just as red cells function for a hundred days or target. From being the (hypothetical allelic) cause of each more without a nucleus. It would therefore be more correct phenotype character, such as eye colour or number of to say that genes are not active causes; they are, rather, limbs, the developments in molecular biology have led caused to give their information by and to the system that to its being defined more narrowly and specifically as a activates them. The only kind of causation that can be DNA sequence that is used by the cell as a template for the attributed to them is passive, much in the way a computer synthesis of a protein or RNA. These are not at all the same program reads and uses databases. The selfish gene idea thing when it comes to questions like ‘what do genes do?’ therefore has to be interpreted not only as a metaphor, but and ‘what kind of causation is involved?’ When Johannsen as one that struggles to chime with modern biology. That (1909) introduced the term ‘gene’ it was defined as the is where the difficulties begin. (necessary) cause of a phenotype, since it was defined as an Ideas that incorporate or are based on metaphors have inherited phenotype that could be attributed to an allele. a very different relationship to empirical discovery than But now it has to be shown to be a cause, and the nature do standard scientific hypotheses with clear empirical of that causation needs clarification. The full implications consequences that ensure their falsifiability. There are of this difference are explained elsewhere (Noble, 2008). several ways in which this is evident. They are reinforced by the fact that most changes at the First, different or even opposing metaphors can both level of DNA do not have a measurable phenotypic effect be ‘true’. This is because metaphors highlight different under normal physiological conditions (see, for example, aspects of the target to which they are applied, a fact that Hillenmeyer et al. 2008). By the original definition, these has long been familiar to metaphor theorists (Lakoff & would not even have been identified as genes, since a Johnson, 1980; Kittay, 1987). Metaphors can correspond gene was an entity that necessarily had a phenotypic to different, even incompatible, aspects of reality. That manifestation. is why, when comparing ‘selfish’ genes with ‘prisoner’ or In this article, I frequently refer to the selfish gene idea ‘cooperative’ genes, as I do in chapter 1 of The Music as a story since one of the questions I am addressing is of Life (Noble, 2006), there is no empirical test that will whether it is more than a story or viewpoint. Colourful unequivocally show which is correct, a point which was metaphorical stories can be highly influential: no-one can conceded long ago by Richard Dawkins at the beginning deny that the selfish gene idea has had a huge impact on the of his book The Extended Phenotype: ‘I doubt that there way in which both lay people and scientists view genetics, is any experiment that could prove my claim’ (Dawkins, including the social implications (Midgley, 2010). Most 1982, p. 1). This point is analogous to the sense in which of the time, people accept its implied scientific basis. It is no experiment could ever disprove a geometry, whether important therefore to ask whether the idea could be inter- Euclidean or not (Poincar´e, 1902, 1968). Significantly, preted as an empirical scientific hypothesis, particularly Dawkins uses a geometric illusion (the Necker Cube) to since Dawkins’s own initial interpretation was that it illustrate his point. was not metaphorical; in reply to Midgley (1979) he (The Extended Phenotype was an even stronger wrote: ‘that was no metaphor. I believe it is the literal statement of the selfish gene idea since it argued that “the truth, provided certain key words are defined in the phenotypic effects of a gene. . .may extend far outside the particular ways favoured by biologists’ (Dawkins, 1981). body in which the gene sits” (Dawkins, 1982, p. vi) Even But a metaphor does not cease to be a metaphor simply effects “at a distance” are seen as being “for the benefit” of because one defines a word to mean something other than the selfish gene.) its normal meaning. Indeed, it is the function of metaphor Second, metaphors often appear circular if interpreted to do precisely this. So, we must first clarify what the idea like a scientific theory. I will show that the selfish gene means. metaphor shows this circularity.  C 2011 The Author. Journal compilation  C 2011 The Physiological Society 1010 D. Noble J Physiol 589.5 Finally, even though there may be no single empirical many other strange new entities in their theories. Without fact that will distinguish between very different metaphors, an empirical handle they might as well not exist. Indeed, this does not mean that empirical discovery has no impact one of the arguments about string theory, for example, on our choice of metaphor. The relationship is more is precisely whether it has satisfied this fundamental nuanced than it may be for most scientific theories. It will criterion. usually require a judgment based on a large set of empirical Moreover, including reference to effectiveness, which in facts to arrive at a conclusion. Much of the meaning evolutionary theory could be interpreted to be fitness, is associated with metaphorical statements is determined surely the most relevant way to gain empirical leverage. by viewpoints that are a matter of personal choice, even We can measure changes in gene copies in a population. though influenced by empirical facts. I will illustrate this Now the question becomes whether we can develop the later in this paper. theory a bit further to become predictive. What, in a gene, could tell us whether or not it is selfish in this sense? On the original definition of a gene as a hypothetical What does ‘selfish’ mean in the selfish gene story? cause of a particular phenotype, this would have been fairly First we must decide whether ‘selfish’ defines a property straightforward. We could look, at the functional level of that is universal to all genes (or even all DNA sequences) the phenotype, for the reasons why a particular function or whether it is a characteristic that distinguishes some would be adaptive. This is in practice what defenders of the DNA sequences from others. This is not as easy as it may selfish gene idea do. They refer to the gene (more strictly an seem. I suspect that the original intention was that all allele) as ‘the gene for’ X or Y, where these are functional, genes could be represented as ‘seeking’ their own success phenotype characters. The phenotype view creeps back in in the gene pool, regardless of how effective they might through the terminology. Any ‘selfishness’ lies at least as be in achieving this. One reason for thinking this is that much in the phenotype as in the genes. so-called junk DNA is represented in the selfish gene story But since we now define genes as particular DNA as an arch-example of selfishness: hitching a ride even with sequences, what in a DNA sequence could possibly tell no function. us whether or not it is selfish? The answer is obvious: But on that interpretation, the demonstration that the the sequences of Cs, Gs, As and Ts could never, by concept is of no utility in physiological science is trivially themselves, give us a criterion that would enable us to easy. Interpreted in this way, a gene cannot ‘help’ being predict that the frequency of that sequence will increase selfish. That is simply the nature of any replicator. But in the gene pool. A DNA sequence only makes sense in since ‘selfishness’ would not itself be a difference between the context of particular organisms in which it is involved successful and unsuccessful genes (success being defined in phenotypic characteristics which can be selected for. here as increasing frequency in the gene pool), nor between A sequence that may be very successful in one organism functional and non-functional genes, there would be no and/or environment, might be lethal in another. This is cashable value whatsoever for the idea in physiology. evident in the fact that almost all cross-species clones do Physiologists study what makes systems work. It matters not form an adult (see later for an important exception). to us whether something is successful or not. Attributing The same, or similar, DNA sequence may contribute to selfishness to all genes therefore leaves us with nothing different, even unrelated, functions in different species. we could measure to determine whether ‘selfishness’ is The sequence, intrinsically, is neutral with regard to such a correct attribute. As metaphor, it may work. But as a functional questions. scientific hypothesis it is empty. The price therefore of giving the selfish gene idea some Could we rescue the idea for physiological science? I empirical leverage is to reveal yet again, though in a doubt whether anyone would want to do that ab initio, different way, that it is an empty hypothesis. There is but we live in a scientific culture that is now thoroughly no criterion independent of the only prediction that the permeated by the idea, and in a way that has strongly hypothesis makes, i.e. that selfish genes increase their disfavoured physiology. The idea has either to be rejected number. It is a strange hypothesis that uses its own or assimilated. One option would be to re-interpret definition of its postulated entity as its only prediction. selfishness to include reference to effectiveness. We could, At this point, I suspect that a defender of the concept for example, say that genes whose numbers of copies would shift back to referring to genes as hypothetical increase are selfish, or more selfish than their competitors. entities, defined as the cause(s) of particular phenotypes. This move would give us an empirical handle on the Note, though, that this is to abandon the purely ‘genes-eye’ idea. view since it shifts the focus back to the phenotype. It is a standard move in science to unpack a metaphor or As a physiologist, naturally I would say ‘so it should’. simile in this way. Physicists make similar moves when they I will discuss the consequences of that shift in a later give empirical criteria for black holes, quarks, strings and section.  C 2011 The Author. Journal compilation  C 2011 The Physiological Society J Physiol 589.5 Neo-Darwinism, the Modern Synthesis and selfish genes 1011 How is the selfish gene story related forming DNA or RNA sequences. All other aspects of the to the central dogma? way in which the dogma has been extended to buttress neo-Darwinism have been deconstructed – by molecular In one of the central paragraphs of The Selfish Gene (page biology itself. Shapiro’s (2009) article is the best account 21), Dawkins writes: of the demolition from a biochemical viewpoint, while Now they swarm in huge colonies, safe inside gigantic Werner (2005) does so from an informatics perspective. lumbering robots, sealed off from the outside world, communicating with it by tortuous indirect routes, manipulating it by remote control. They are in you and Are genes the only immortals? me; they created us, body and mind; and their preservation is the ultimate rationale for our existence. A central distinction in the selfish gene story is that between replicators and vehicles. The distinction is based The phrase ‘sealed off from the outside world’ is a on considering inheritance only of changes. While the colourful statement of the idea that genes are uninfluenced vehicle is also ‘inherited’ (genes on their own do nothing by their environment, a view that was strongly buttressed and certainly are not sufficient to ‘make’ an organism – by the central dogma of molecular biology, originally since we must also inherit a complete fertilised egg cell), the formulated by Crick (1958, 1970) and taken to exclude story goes that changes in the vehicle are not inherited (so information flow other than from genes to proteins. no inheritance of acquired characteristics) while changes in In fact, of course, what the molecular biology showed the replicator (e.g. mutations) are inherited. This approach was simply that amino acid sequences are not used is what enables the wholesale inheritance of the vehicle to as templates for forming nucleic acid sequences. The be ignored. unjustified extension was to think that information cannot Yet, the vehicle (the cell, or each cell in a multicellular pass from proteins to nucleic acids, whereas this is pre- organism) clearly does reproduce (indeed, it is only cisely what must happen for genes to be activated and for through this reproduction that DNA itself is trans- expression patterns to be formed. This extension (which mitted), and in doing so it passes on all the phenotype can be seen in phrases like “the inheritance of instructively characteristics for which there are no nuclear DNA acquired adaptation would violate the ‘central dogma’ of templates and which are necessary to interpret the embryology” (Dawkins, 1982, p. 173) was a godsend to inherited DNA. An obvious example is the transmission the neo-Darwinists since it provided a basis, right down at of mitochondria, chloroplasts and other organelles, which the level of DNA itself, for regarding genes as ‘sealed off’ almost certainly originated as symbionts (‘invading’ or from the outside world. The original experimental basis ‘engulfed’ bacteria) at an early stage of evolution when for this idea was the Weismann (1893) barrier. eukaryotes were first formed. Many other transmitted A godsend, except that it is not correct in the relevant cytoplasmic factors also exist (Sun et al. 2005; Maurel & sense, and never has been. Even at the time the dogma was Kanellopoulos-Langevin, 2008). All these replicate and, in formulated, it was sufficient to ask the question how do the selfish gene story would have to be given the status of different cells in the body, with exactly the same genome, ‘honorary genes’. end up as different as bone cells and heart cells? The answer The existence of such cellular inheritance requires the of course is that the way in which the genome is read leads selfish gene theory to distinguish between replication and to completely different patterns of gene expression. This reproduction. The next step in the story is to claim that requires flow of information onto the genome itself, which, replicators are potentially immortal, whereas reproducers as Barbara McClintock (1984) said, should be regarded as are not. an ‘organ of the cell’, not its dictator. There are feedbacks Biologically speaking, this is evident nonsense. Through and restraints, not only between the products of the genes germline cells I am connected via many reproductions (which might be consistent with a genes-eye view), but to the earliest cells, even to those without genomes. In right down onto the genome itself, determining when, some sense, the cell as a whole has achieved at least where and how much of each gene product is formed. equivalent immortality to that of its DNA. Cells, even As Beurton et al. (2008) comment ‘it seems that a cell’s those without genomes in the postulated pre-DNA world enzymes are capable of actively manipulating DNA to do of RNA enzymes (Maynard Smith & Szathm´ary, 1999), this or that. A genome consists largely of semistable genetic clearly reproduce themselves, and in doing so they also elements that may be rearranged or even moved around pass on any differences among them (Sonneborn, 1970; in the genome thus modifying the information content of Sun et al. 2005). Any difference between replication and DNA.’ reproduction (which, after all, are just synonyms; the The central dogma, as a general principle of biology, has distinction is a linguistic confusion) does not entitle one therefore been progressively undermined. The only aspect to say that one is immortal and the other is not. What of it still left intact is its original strictly chemical sense, were all those cells without genomes doing in early life i.e. that protein sequences are not used as templates for on earth? We wouldn’t be here to tell the story if they  C 2011 The Author. Journal compilation  C 2011 The Physiological Society 1012 D. Noble J Physiol 589.5 did not also form an ‘immortal line’. As I have argued of the roles of the protein it codes for in higher-level elsewhere (Noble, 2008) the main difference between DNA functions can reveal that. That will include identifying the and non-DNA inheritance is simply that one is digital, real biological regulators as systems properties. Knockout the other analog. In developing the organism the 3D experiments by themselves do not identify regulators analog information is just as necessary as the 1D digital (Davies, 2009). (DNA) information. Neither is sufficient by itself. They are So, the view that we can only observe differences in mutually dependent. The amount of analog information phenotype correlated with differences in genotype both can also be calculated to be comparable to that of the leads to incorrect labelling of gene functions and falls into genome (Noble, 2011). Moreover, organisms are not in the fallacy of confusing the tip with the whole iceberg. We fact digital machines (Shapiro, 2005; Noble, 2010a). want to know what the relevant gene products do in the organism as a physiological whole, not simply by observing differences. Remember that most genes and their products, The genetic differential effect problem RNA and proteins, have multiple functions. Clearly, many of the problems with the selfish gene story To see the poverty of the view that we can only observe arise from unusual or imprecise use of the language differences, just ask the question what engineer would be of genetics, leading to untestable ideas. Another central satisfied simply to know the difference between the cement muddle, both in neo-Darwinism and in the selfish gene he used this time to construct his building compared to story, is what I have called ‘The genetic differential effect what he used previously, or to know just the differences problem’ (Noble, 2008, 2011), the idea that genetics is only between two electronic components in an aircraft? Of about differences. This view is now unsustainable, since course, he might use the difference approach as one of defining genes as DNA sequences clearly does identify his experimental tools (as genetics has in the past, to a specific chemical entity whose effects are not merely good effect), but the equations and models of an engineer attributable to differences in the sequence. We can say represent the relevant totality of the function of each precisely for which proteins or RNAs the sequence acts as component of a system. So does physiological analysis a template and analyse the physiological effects of those of function, which is why physiology cannot be restricted proteins or RNAs. The arguments for abandoning the to the limitations of the ‘difference’ approach. difference perspective are overwhelming (see also Longo Second, accurate replication of DNA is itself a system & Tendero, 2007). property of the cell as a whole, not just of DNA. DNA Differences in DNA do not necessarily, or even usually, on its own is an extremely poor replicator. It requires result in differences in phenotype. The great majority, a dedicated set of proteins to ensure correction of 80%, of knockouts in yeast, for example, are normally transcription errors and eventual faithful transmission. ‘silent’ (Hillenmeyer et al. 2008). While there must be Both in ensuring faithfulness of DNA replication and underlying effects in the protein networks, these are in creating robustness against genetic defects, systems clearly buffered at the higher levels. The phenotypic effects properties are the important ones. The cell as a whole therefore appear only when the organism is metabolically ‘canalises’ the way in which DNA is interpreted, making it stressed, and even then they do not reveal the precise robust and reproducible. The famed ‘immortality’ of DNA quantitative contributions for reasons I have explained is actually a property of the complete cell. elsewhere (Noble, 2011). The failure of knockouts to The distinction between replicator and vehicle is systematically and reliably reveal gene functions is one therefore out of date from a physiologist’s viewpoint. It of the great (and expensive) disappointments of recent stems from the original ‘genetic program’ idea, in which biology. Note, however, that the disappointment exists organisms are viewed as Turing machines with the DNA only in the gene-centred view. By contrast it is an exciting being the digital tape of the computer (tape–computer challenge from the systems perspective. This very effective is much the same distinction as replicator–vehicle – this ‘buffering’ of genetic change is itself an important systems was the basis of Jacob and Monod’s concept of the property of cells and organisms. ‘genetic program’; Jacob, 1970). Organisms are interaction Moreover, even when a difference in the phenotype does systems, not Turing machines (Shapiro, 2005; Noble, become manifest, it may not reveal the function(s) of the 2008). There is no clear distinction between replicator gene. In fact, it cannot do so, since all the functions shared and vehicle (Coen, 1999). between the original and the mutated gene are necessarily Finally, the story implies that the ‘vehicles’ do not hidden from view. This is clearly evident when we talk of themselves evolve independently of their DNA. There is oncogenes. What we mean is that a particular change in no reason why this should be true. In fact it is certainly DNA sequence predisposes to cancer. But this does not tell false. Egg cells from different species are different. So us the function(s) of the un-mutated gene, which would be much so that cross-species hybrids using nuclear trans- better characterised in terms of its physiological function fer usually do not survive, and those that do, as in the in, e.g., the cell cycle. Only a full physiological analysis elegant experiments of Sun et al. (2005) – see Fig. 2 –  C 2011 The Author. Journal compilation  C 2011 The Physiological Society J Physiol 589.5 Neo-Darwinism, the Modern Synthesis and selfish genes 1013 transferring nuclei between different fish species, reveal move on from the restrictions of the differential approach. precisely the influence of the species-specific cytoplasmic The integrative approach can achieve this by reverse factors on development (see also Jaenisch, 2004; Yang engineering using computational modelling, as I have et al. 2007). Crossing a common carp nucleus with a shown elsewhere (Noble, 2011). The genes-eye view is only goldfish enucleated egg cell produces an adult fish that one way of seeing biology and it doesn’t accurately reflect has an intermediate shape and a number of vertebrae much of what modern biology has revealed. In fact, its closer to that of the goldfish. These factors can therefore central entity, the gene, ‘begins to look like hardly definable determine a phenotype characteristic as fundamental as temporary products of a cell’s physiology’ (Beurton et al. skeletal formations. Over 50 years ago, McLaren & Michie 2008). (1958) showed a similar phenomenon as a maternal effect Finally, I want to return to the role of metaphor and the in mice. The number of tail vertebrae (4 or 6 in the selfish gene idea. different strains) was determined by the surrogate mother, When I first read Richard Dawkins’s acknowledgement not the embryo. Of course, such cytoplasmic influences are in The Extended Phenotype (‘I doubt that there is any dependent on the DNA of the mother, but these influences experiment that could be done to prove my claim’) I will necessarily include patterns of gene expression that was strongly inclined to agree with it (both in relation to are also dependent on other influences. There is inter- the original selfish gene idea and its development in The play here between DNA and non-DNA inheritance, as Extended Phenotype) since, if you compare the selfish gene there must always be. Moreover, maternal and paternal metaphor with very different metaphors, such as genes effects in response to the environment have been shown as prisoners, it is impossible to think of an experiment to be transmitted down two generations (grandparents to that would distinguish between the two views, as I argued grandchildren) in humans (Pembrey et al. 2006) and could earlier in this paper. For any given case, I still think that therefore be a target for natural selection. must be true. But I have slowly changed my view on whether this must be true if we consider many cases, looking at the functioning of the organism as a whole. Conclusions There are different ways in which empirical discovery can As physiological and systems biological scientists, we need impact on our theoretical understanding. Not all of these to reconnect to evolutionary theory. It was difficult to are in the form of the straight falsification of a hypothesis, a do this during most of the 20th century because the point that has been well-understood in theoretical physics neo-Darwinist synthesis more or less excluded us, by for many years (Poincar´e, 1902, 1968). Sometimes it is relegating the organism to the role of a disposable vehicle. the slow accumulation of the weight of evidence that It also, unjustifiably, excluded Lamarck (Noble, 2010b). eventually triggers a change of viewpoint. This is the case Darwin himself was not so sure; in the first edition of with insights that are expressed in metaphorical form (like The Origin of Species (Darwin, 1859) he wrote ‘I am ‘selfish’ and ‘prisoners’), and that should not be intended convinced that natural selection has been the main, but to be taken literally. The first mistake of the differential not the exclusive means of modification’, a statement he approach was to interpret the selfish gene idea as literal reiterated with increased force in the 1872, 6th edition. truth. It is clearly metaphorical metaphysics, and rather As many evolutionary biologists now acknowledge, the poor metaphysics at that since, as we have seen, it is Modern Synthesis (neo-Darwinism) requires extending essentially empty as a scientific hypothesis, at least in (Jablonka & Lamb, 2005; Pigliucci & Muller, 2010b). physiological science. But in social evolution also, the idea If physiology is to make the contribution it should is simply one of several viewpoints that can account for to the fields of evolution and development, we need to the same data (Okasha, 2010). Figure 2. Cross-species clone The nucleus of a common carp, Cyprinus carpio (middle), was transferred into the enucleated egg cell of a goldfish, Carassius auratus (left). The result is a cross-species clone (right) with a vertebral number closer to that of a goldfish (26–28) than of a carp (33–36) and with a more rounded body than a carp. The bottom illustrations are X-ray images of the animals in the top illustration. Figure kindly provided by Professor Yonghua Sun from the work of Sun et al. (2005).  C 2011 The Author. Journal compilation  C 2011 The Physiological Society 1014 D. Noble J Physiol 589.5 The weight of evidence in the physiological sciences Goldenfeld N & Woese C (2011). Life is physics: Evolution as a is now much more favourable to the metaphor of collective phenomenon far from equilibrium. Annu Rev ‘co-operation’ than of ‘selfishness’. Gene products all Cond Matt Phys 2 (in press). co-operate in robust networks one of whose functions Gould SJ (2002). The Structure of Evolutionary Theory, (see ch. is precisely to insulate the organism from many of the 8, especially pp. 673–714). Harvard University Press, Cambridge, MA, USA. vagaries of gene mutation, and stochasticity at lower levels. Hillenmeyer ME, Fung E, Wildenhain J, Pierce SE, Hoon S, Lee Investigating these networks and their mechanisms is the W, Proctor M, St Onge RP, Tyers M, Koller D, Altman RB, way forward. Davis RW, Nislow C & Giaever G (2008). The chemical It is therefore time to move on and remove the genomic portrait of yeast: uncovering a phenotype for all conceptual barriers to integrating modern physiological genes. Science 320, 362–365. science with evolutionary and developmental theory. The Hunter P, Smaill BH, Smith NP, Young A, Nash M, Nielsen PF, integrative approach can achieve this since it avoids Vaughan-Jones RD, Omholt S & Paterson DJ (2011). The the simplistic fallacies of the gene-centred differential Heart Physiome Project. WIRE Syst Biol Med (in press). approach and it is essentially what successful systems Huxley JS (1942). Evolution: The Modern Synthesis. Allen & physiology has employed for many years. Unwin, London. Jablonka E & Lamb M (2005). Evolution in Four Dimensions. MIT Press, Cambridge, MA, USA. Further reading Jacob F (1970). La Logique du vivant, une histoire de l’h´er´edit´e . Gallimard, Paris. This article has been written for a physiological readership Jaenisch R (2004). Human cloning – the science and ethics of that may not be very familiar with the current debates in nuclear transplantation. New Engl J Med 351, 2787–2791. evolutionary and genetic theory. If you learnt evolutionary Johannsen W (1909). Elemente der Exakten Erblichkeitslehre. biology and genetics a decade or more ago you need to be Gustav Fischer, Jena. Keeling PJ & Palmer JD (2008). Horizontal gene transfer in aware that those debates have moved on very considerably, eukaryotic evolution. Nat Rev Genet 9, 605–618. as has the experimental and field work on which they are Keller EF (2000). The Century of the Gene. Harvard University based. Amongst the references cited, the following may Press, Cambridge, MA, USA. help the reader to catch up: Margulis (1998); Jablonka & Kittay EF (1987). Metaphor: Its Cognitive Force and Linguistic Lamb (2005); Noble (2006); Okasha (2006); Beurton et al. Structure. Oxford University Press, Oxford. (2008); Shapiro (2009); Pigliucci & M¨uller (2010b). For Kohl P, Crampin E, Quinn TA & Noble D (2010). Systems those interested in the philosophical and social impacts of biology: an approach. 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I should like to acknowledge long and deep discussions Poincar´e H (1902, 1968). La science et l’hypoth`ese. Flammarion, with the organisers of the Balliol College, Oxford semi- Paris. nars on conceptual foundations of Systems Biology: Romanes GJ (1883). Letter to the Editor. Nature 27, 528–529. Jonathan Bard, Tom Melham and Eric Werner; and the Shapiro JA (2005). A 21st century view of evolution: genome organisers and participants of the ‘Homage to Darwin’ debate system architecture, repetitive DNA, and natural genetic engineering. Gene 345, 91–100. (http://www.voicesfromoxford.com/homagedarwin part1.html) Shapiro JA (2009). Revisiting the central dogma in the 21st held in Oxford in May 2009: Stephen Bell, Martin Brasier, century. Ann N Y Acad Sci 1178, 6–28. Richard Dawkins and Lynn Margulis. I received criticism of Sonneborn TM (1970). Gene action on development. Proc R early drafts of this paper from David Vines, David Cleevely, Soc Lond B Biol Sci 176, 347–366. Nicholas Beale and Stig Omholt. I also acknowledge discussions Sun YH, Chen SP, Wang YP, Hu W & Zhu ZY (2005). with Peter Kohl, Ray Noble and James Shapiro. Providing Cytoplasmic impact on cross-genus cloned fish derived from valuable input and feedback does not of course signify assent to transgenic common carp (Cyprinus carpio) nuclei and the claims of my paper. I consulted on a wide range of opinion. goldfish (Carassius auratus) enucleated eggs. Biol Reprod 72, Work in the author’s laboratory is funded by the PreDiCT 510–515. project of the European Union under FP7.  C 2011 The Author. Journal compilation  C 2011 The Physiological Society