Epigenetics Landscape (Fig

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Conrad Waddington and ‘decisions’ that could be represented as exploited plasticity that is already ‘valleys’ and ‘forks’ in a developmental present in the population. That strongly the origin of epigenetics landscape (Fig. 1). He knew from his suggests that all the alleles (gene developmental studies that embryo fruit variants) necessary for the inheritance of flies could be persuaded to show different the characteristic were already present in thorax and wing structures, simply by the population, but not initially in any changing the environmental temperature or particular individuals in the correct by a chemical stimulus. In his landscape combination. The experiment simply diagram, this could be represented as a brings them together. This is a small manipulation in slope that would lead modification of the pattern of the genome to one channel in the landscape being in response to the environmental change, favoured over another, so that the adult but not in a way that requires any new could show a different phenotype starting mutations. I came to this conclusion from the same genotype. before reading Waddington’s (1957)

Epigenetics book, The Strategy of the Genes. But it is Denis Noble discusses Conrad The next step in his experiment was to in fact one of Waddington’s own ideas! Waddington’s classic paper, ‘The genetic select for and breed from the animals that He writes ‘There is no … reason which ’ assimilation of the bithorax phenotype , displayed the new characteristic. Exposed would prevent us from imagining that all published in Evolution in 1956. to the same environmental stimulus, these the genes which eventually make up the assimilated genotype were already In 1956, the British developmental gave rise to progeny with an even higher proportion of adults displaying the new present in the population before the biologist, Conrad Waddington, published a selection began, and only required paper in the journal Evolution character. After a relatively small number of generations, he found that he could then bringing together’ (p.176).Notonly (Waddington, 1956) in which he succeeded does he clearly see this possibility, he in demonstrating the inheritance of a breed from the animals and obtain robust inheritance of the new character even also tests it. He continues (p. 178) characteristic acquired in a population in ‘Attempts to carry out genetic response to an environmental stimulus. without applying the environmental stimulus. The characteristic had therefore assimilation starting from inbred lines Much earlier, in 1890, August Weismann have remained quite unsuccessful. This had tried and failed to achieve this. He become locked into the genetics of the animal. He called this process genetic provides further evidence that the amputated the tails of five successive process depends on the utilisation of generations of mice and showed absolutely assimilation. What he had succeeded in showing was that an acquired characteristic genetic variability in the foundation no evidence for an effect on subsequent ’ ’ could first be inherited as what we would stock with which the experiment begins . generations. Weismann s discovery that the ‘ ’ Histextcouldnotbeclearer. effects of an environmental stimulus (tail now call soft inheritance, and that it could then be assimilated into becoming standard amputation) cannot be transmitted to ‘ ’ subsequent generations, together with his hard genetic inheritance. Today, we call Orthodox Neo-Darwinists dismissed ‘ ’ ’ assumption that genetic change is random, soft inheritance epigenetic inheritance, Waddington sfindingsasmerelyan formed the foundations of the Modern and of course, we know many more example of the evolution of phenotype Synthesis (Neo-Darwinism) of our mechanisms by which the same genome plasticity. That is what you will find in understanding of genetic inheritance. can be controlled to produce different many of the biology textbooks even today epigenetic effects. (e.g. Arthur, 2010). I think that Waddington Waddington’s approach, however, was showed more than that. Of course, plasticity much more subtle and more likely to be What was happening at the gene level in can evolve, and that itself could be by a successful because he realised that the way Waddington’s experiments? A standard Neo-Darwinist or any other mechanism. to test for the inheritance of acquired Neo-Darwinist explanation might be that But Waddington was not simply showing characteristics is first to discover what some mutations occurred. That is possible, the evolution of plasticity in general; he was forms of developmental plasticity already but extremely unlikely on the time scale of showing how it could be exploited to enable exist in a population, or that the population the experiment, which was only a few a particular acquired characteristic in could be persuaded to demonstrate with a generations. Moreover, random mutations response to an environmental change to be little nudging from the environment. By would occur in individuals, not in a whole inherited and be assimilated into the exploiting plasticity that already existed he group. Single small mutations would have genome. Moreover, he departed from the was much more likely to mimic a path that taken very many generations to spread strict Neo-Darwinist view by showing that evolution itself could have taken. through whole populations, and many such this could happen even if no new mutations mutations would have been required. occur (Fig. 2). He used the word ‘canalised’ for this kind of persuasion since he represented the But I think there is a much simpler Epigenetics means ‘above genetics’ developmental process as a series of explanation. Recall that the experiment and it was originally conceived by

Classics is an occasional column, featuring historic publications from the literature. These articles, written by modern experts in the field, discuss each classic paper's impact on the field of biology and their own work. The Journal of Experimental Biology

816 CLASSICS The Journal of Experimental Biology (2015) 218, 816-818 doi:10.1242/jeb.120071

AB reasons why I became interested in evolutionary biology many years ago, and why I have also explored ways in which evolutionary theory can be integrated with recent discoveries in molecular and physiological biology (Noble et al., 2014).

Waddington’s concepts are also highly ’ Fig. 1. Waddington s developmental landscape diagram. The landscape itself and the ball at the top relevant to biologists interested in the are from his original diagram. The subsequent positions of the ball have been added to illustrate his point that development can be canalised to follow different routes (A and B). The plasticity to enable this to ways in which organisms adapt to their happen already exists in the wild population of organisms (modified diagram by K. Mitchell). environment, and to comparative biologists interested in how this varies Waddington himself to describe the also true to say that Lamarck did not between species. Many of the ways in existence of mechanisms of inheritance invent the idea of the inheritance of which modern epigenetics plays an in addition to (over and above) standard acquired characteristics. But, whether essential role in these fields have been genetics (Bard, 2008). Waddington historically correct or not, we are stuck described in a special issue of this journal regarded himself as a Darwinist since today with the term ‘Lamarckian’ for (see overview by Knight, 2015). The Darwin also, in The Origin of Species, inheritance of a characteristic acquired discovery of epigenetic marking of DNA included the inheritance of acquired through an environmental influence. and its associated chromatin proteins has characteristics. But significantly, opened up new vistas for experimental Waddington was not a Neo-Darwinist Waddington’s concepts of plasticity and biology. since Neo-Darwinism, following epigenetics have been very influential in Weismann, specifically excludes such my own thinking about experiments on I conclude this article with a warning: inheritance. Waddington was a cardiac rhythm. We found that the heart’s if you are inspired to try to repeat profound thinker about biology, and pacemaker is very robust, so much so that Waddington’s 1956 experiment, do much else too. The Strategy of the protein mechanisms normally responsible remember that you will fail if you try to do Genes is a masterly account of the for a large part of the rhythm could be it on a cloned laboratory population. The many reasons why he dissented from completely blocked or deleted (Noble mechanism depends on using a wild Neo-Darwinism, and it has stood the et al., 1992). Only very small changes in population with natural genetic diversity. test of time. It was reprinted over half a rhythm occur, because other mechanisms In this respect it resembles a phenomenon century later, in 2014. He did not come into play to ensure that pacemaker first noted by James Baldwin (1896). This describe himself as a Lamarckian, but activity continues. The relation between is that individuals in a population with the by revealing mechanisms of inheritance individual genes and the phenotype is ‘correct’ allele combinations could of acquired characteristics, I think he therefore mediated through networks of choose a new environment and so should be regarded as such. The reason interactions that can buffer individual permanently change the evolutionary he did not do so is that Lamarck could gene variation, just as Waddington development in that environment. It not have conceived of the processes that envisaged in his diagrams of epigenetic resembles Waddington’s idea, as he Waddington revealed. Incidentally, it is effects and canalisation. This is one of the himself recognised, because it does not require new mutations. More recently, Karl Popper, the great logician of science, Influence of environment also noted the possible importance of genetic assimilation without mutations in evolutionary theory (Niemann, 2014; Noble, 2014). Popper and Waddington had both taken part in discussions on Developmental evolutionary biology during the 1930s landscape and 1940s when the field of molecular biology was still developing (Niemann, 2014).

While celebrating the recent rapid rise in epigenetics research (see Hoppeler, 2015; Functional networks Knight, 2015), let’s also celebrate the father of epigenetics, Conrad Genes Waddington, who opened our eyes to the rich opportunities of adaptation through Fig. 2. Waddington’s diagram to show how the developmental landscape relates to individual epigenetic regulation. genes (bottom pegs) through networks of interactions in the organism. Since he also showed the influence of the external environment on canalisation of development, I have extended the diagram by Denis Noble adding the top part to represent the environmental influences. It is the combination of these influences University of Oxford that can lead to an evolutionary change without mutations (modified from Waddington, 1957). [email protected] The Journal of Experimental Biology

817 CLASSICS The Journal of Experimental Biology (2015) 218, 816-818 doi:10.1242/jeb.120071

References Knight, K. (2015). A comparative perspective on atrial node cells. Proc. R. Soc. B. Biol. Sci. 250, Arthur, W. (2010). Evolution, A Developmental epigenetics. J. Exp. Biol. 218, 1-5. 199-207. Approach. Oxford, UK: Wiley Blackwell. Niemann, H.-J. (2014). Karl Popper and The Two Noble, D., Jablonka, E., Joyner, M. J., Müller, Baldwin, J. M. (1896). A new factor in evolution. New Secrets of Life.Tübingen: Mohr Siebeck. G. B. and Omholt, S. W. (2014). Evolution Am. Nat. 30, 441-451. Noble, D. (2014). Secrets of life from beyond the evolves: physiology returns to centre stage. Bard, J. B. L. (2008). Waddington’s legacy to grave. Physiol. News 97, 34-35. J. Physiol. 592, 2237-2244. developmental and theoretical biology. Biol. Noble, D., Denyer, J. C., Brown, H. F. and Waddington, C. H. (1956). The genetic assimilation Theory 3, 188-197. DiFrancesco, D. (1992). Reciprocal role of the of the bithorax phenotype. Evolution 10, 1-13. Hoppeler, H. H. (2015). Epigenetics in comparative inward currents ib,Na and if in controlling and Waddington, C. H. (1957). The Strategy of the physiology. J. Exp. Biol. 218,6. stabilizing pacemaker frequency of rabbit Sino- Genes. London: Allen and Unwin. Reprinted 2014. The Journal of Experimental Biology

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