 Felly mae yw weld cyntaf i'r gweithgwysydd a chysylltu gyda'r gweithgu a'r llei i anisech chi'n gweithgwysydd. Pan hwn wedyn i'w gweithio meddylion yma am y gwybod dda i mewn wasith yn y Rhubd Ystod, byddwn chi'n gweithio beth yw hwn y mwy yn yn 8 o 9. Felly unrhyw rydw i'n dweud ymddangos ystod, yma maeth ar y cyf cyfwil yn 80% gweithgwysydd a 20% gyfeithgwysydd. C striking, mae'r padwn yn yn iawn yn 40 oes o'r ddigon, rhai ddechrau'r ddaeth hynny o'i'r dalig rwy'n gwrdd ystod ystod o'r perian yn gwahol – mwyn i ysgol oherwydd ei wneud drwy'r digon ar gyfer gafydd gyda'r rhan. Ond gweithio i nhw'n meddwl, mae'n ffaseniatwg oedd yn yn 40 oes o'r ddigon, mae'n meddwl a bod sut 40 yw ddaint y gallwn yn dweud i gweithio'rhelod pantermineb rhai a ddaw'n dweud ym Lleodraeth Cymru, oedd y ddwyd yn cael ei gŵn. Dweud yn bryddoedd chi'n gweithio'r ddysguys ifanc a'ri yn bryd i gael llwyth hwnnw, Un o hynny, ydych chi'n bwysig i Professor George David Smith. He is our Professor of Clinical Epidemiology at the University of Bristol, and a major focus of George's work has been on the influence of childhood socioeconomic deprivation on later morbidity and mortality, so the patterns of morbidity and mortality in adult life. George has published over 700 peer-reviewed journal articles, 15 or so books and edited collections, but being a modern man, you will also find him on YouTube explaining Mendelian randomisation. Over the past five to ten years, George has really been at the forefront of development and application of Mendelian randomisation approaches, where genetics is used in really quite a sophisticated way to try and understand more about the causal role of behavioural factors in explaining different health outcomes. Now, I know George partly because he's the co-editor of the International Journal of Epidemiology, which is a publication where lots of cohort research is published, but also because he's the scientific director of the Avon Longitudinal Study of Parents and Children, which is one of the nine cohort studies that Jude was talking about. So, I'm really pleased to be able to give the floor to George. Please welcome him. So, it's a great pleasure to be here. As Jane said, I'm an epidemiologist, so I study how environmental factors influence disease. So, the notion that indeed the environment does get under the skin and change of biological beings is not something that is alien to my work. Indeed, it's the entire focus of my work. Maybe the one reason I should be here is that I must be one of the few people who, when they got a grant application rejected from one of their funders, I won't name the funder, one of the referees' comments said that I was a geneticist trying to pretend to be a social scientist, and the other said I was a social scientist masquerading as a geneticist, so that's why I shouldn't be funded. Epigenetics is a great topic for epidemiologists because it is the confused epidemiologist's friend, if ever you're at a meeting and you don't really know what the reason is for something you've found, you can just sort of say that it's epigenetics and you can wave your hands around and everyone sort of nods and says, well, this is a really smart person because no one really knows what it is, the definitions shift. But at the same time, it's become an enormously focused topic of popular science. There's a whole series of popular science books. This is the one I would recommend by Nessa Carey. But they all have titles like The Epigenetics Revolution. The idea is that this is completely changing what we know, or identically different how you can change your genes, spelt with a G, not a J, or the final mystery, isn't that fantastic? There's no future mysteries, this is the final mystery of inheritance. So in fact, my favourite one, because I think it's closer to the truth, which is epigenetics and the age of Twitter because it really is a sort of 30 characters thing. You can just mention epigenetics and as I say, everyone nods. The term comes from epigenesis and epigenesis is simply basically development from zygote onwards, from fertilised cell onwards. So as a single cell, fused two germ cells develops and becomes an organism, then those processes whereby a single cell becomes this millions of cell organism is epigenesis. So it's a process, it's just a process of development. That's where the term comes from. So therefore it's quite odd that you see, for example here in Nature in 2012, stress makes its molecular mark and epigenetics is to blame. So the idea is that there's somehow this sort of process, which is just a process of development, but somehow it has motive force. It's something you can sort of say that this is actually what's driving things. And what I'm going to try and say in my brief period tonight is that epigenesis and epigenetics is part of a process but is not itself something which either fundamentally changes how we understand biological being or social being in my view, nor something that has major motive force. It's part of a process. So epigenetics, what's new, what is part of the revolution and what's true? So with the term epigenetics, one is then talking about the particularities of this process of epigenesis. And these statements are ones which I think, they can be challenged, but I think are true. First, epigenetics refers to processes whereby a single cell is fused zygote with germline DNA, how that goes on to become an organism with kidneys, with livers, with lungs, with brains. And of course they all have the same DNA. What is now clear is, as was absolutely logical one might think, was that 70 years ago or so people thought well maybe the DNA would change and it would get cut down and you'd just have the DNA which makes kidneys in the kidneys or the DNA which makes brain in the brains. But what becomes clear is that all the cells retain their germline DNA but also that their germline DNA can be reactivated. This is why John Gurdin got his Nobel Prize a few years ago and Yamunaka more recently was actually showing that any cell contains the DNA but he can strip it back and it can just become like a primordial cell and become anything. The DNA stays the same but of course there must be changes in how it is expressed which is transmissible across mitosis. A mitosis is when a cell divides in the body when a liver cell becomes a liver cell. Just the cell division which goes when you've got one cell up to you've got these billions of cells in the largest organisms that the cells change and they become differentiated and it moves so you have some liver which when it divides becomes a liver. And when you get disease cells you get a cell in an early stage of lung cancer and when that divides it becomes a cell which has the markers of the early stage of disease or then the later stages of disease. So there's nothing controversial about this, this is just a description of a process and it's a process that we are coming to understand better. So in disease the mitotic transfer, the transfer across cell division is something which occurs and allows disease to be established as well as development to be established. So those things are true. So the technology is what's transformed the work I do because the technologies now exist to actually study these processes at a molecular level. Now this is something which really has dramatically changed over the last decade. It was clear that these processes occurred and they were discussed and there was beginnings to understand it but over the last decade the major processes that we understand biologically which are DNA methylation. This is when you have your germline DNA and parts of it become methylated. This stops those parts being expressed. Well, lots of the DNA which aren't expressed in ways that we know are methylated as well or there's differences in the structural confirmation of the DNA, the histone modifications, what the DNA is packed around or there's tiny RNAs which get passed on in the cytoplasm. These are the sorts of processes we know and they are all now studiable and these are the processes which allow cellular differentiation to occur. It's why you're not just huge zygos, you're not just a huge fertilised eggs that you actually have, livers, brains, kidneys etc etc. Those processes can be studied and also one can see how environmental factors can also influence those processes, in particular DNA methylation. That technology has just transformed beyond all recognition from a decade ago. This actually gives ways of studying mechanisms of gene environment interplay. For example, one can look at how cigarette smoking influences methylation. You see that cigarette smoking influences methylation around a gene which is related to platelet aggregation, those are things in your blood which stick together. That process likely influences how much blood coagulates which then influences heart attacks. This is amazing, one is actually getting down to being able to look at some sorts of biological processes which link the environment to disease. There's also lots of methylation changes which appear to be a happy phenomenon which relate to smoking. As you know, smoking is the cause of all statistics and also it causes huge depth changes in methylation, an area that we're studying. You can actually understand the mechanisms of gene environment interplay in a way that one couldn't investigate those mechanisms previously. Finally, these changes also give some way that there might be some form of vague directionality around where mutations occur in the genome because methylation, in particular during processes of demethylation, there's lots of different forms of methylation that some of those seem to influence whether a mutation is going to occur, a somatic mutation. The sorts of mutations, these are not germline mutations, these are things that are occurring in the cells, I mean that cancers arise, for example. This gives possibly some form of directionality to mutations. These are all true. To me, this is enough, it's made me redirect the topic of areas I study, I'm particularly interested in these and I work a lot on these areas. This isn't why there's excitement about epigenetics. These things are not the reason why there's excitement. The excitement about epigenetics is because of the supposed notion of transgenerational epigenetic inheritance. The idea that somehow something occurring in generations before environmental factors that influence generations before get transmitted down. Darwinian evolution or Mendelian transmission is not what occurs. We have Lamarck on the one hand and we have a giraffe eating on the other hand because you all know it is actually in Lamarck. I actually went back, I thought maybe this was a sort of stereotype but actually in Lamarck's own work he does discuss the notion of the giraffe stretching its neck to eat from the high trees and as the giraffe stretches, little baby giraffe has a slightly longer neck and then down the line you end up with a giraffe with a huge neck. Now of course this was heresy in the post modern synthesis world, the post 1940s, 1930s, 1940s world, although less heretical actually than he's generally stated. This notion that acquired characteristics could be transmitted. The reason why epigenetics hits the headlines is not because of the vastly fascinating areas that we now really understand about epigenesis and epigenetic processes but it's because of this heretical notion, the frisson of Lamarckian heresy. That's why you get the epigenetic heretic Michael Skinner saying these are things in the last couple of weeks and the two highest impact factor are most influential magazines in science, journals in science, this is in science, and this is probably going to be the biggest paradigm shift in science in recent history, and this is the sins of the father, this is from nature, the idea that what your grandad ate is somehow the most important factor going on in terms of how you turn out. This is why there's the excitement. Of course the root of all is Audrey Hepburn, this is the Daily Mail which actually is just about as accurate as nature and science on these topics. It says, is Audrey Hepburn the key to stopping the obesity epidemic? Or epigenetics on Audrey Hepburn, here we go. Audrey gets this right up because she was in Holland during the Dutch hunger winter. This was when the Nazis restricted food supplies in part of Holland towards the end of the Second World War, and Audrey was there. Lots of studies have been done looking at the long-term consequences of this, including things that might be transmitted down the generations. Everything that happened to Audrey has been attributed to this. There she is, she's looking very sweet as a 10-year-old, and there she is smoking, she's a chain smoker. The publicists made sure that no one ever saw this. This is a very rare photograph of someone who smoked 60 a day to be captured smoking a cigarette because the paparazzi found her. The cigarettes might have had an influence on why she was so thin and then why she got cancer, but still everything is now focused on the potential epigenetic influences on Audrey Hepburn. Or this is Der Spiegel, the victory over the genes. Victory over the genes, isn't it wonderful? Smarter, healthier, happier, how we can outwit our genome. Or Newsweek, beyond the book of life, rollover, Mendel, Watson and Crick, they're so your old man's version of DNA, why your DNA isn't your destiny. New Scientist, forget genes or New Scientist again, Darwin was wrong. One of the worst offenders here, The Guardian, which publishes some of the worst stuff in this area actually, why everything you've been told, everything you've been told about evolution is wrong. Now there's so many reasons why this is not true, that one could spend the rest of the evening talking about the reasons why it's not true. But I like people who look like Wilhelm Johansson. He came up with the word gene, so the word that we all know gene. But what Johansson did was vastly more important than the word gene, is he developed the paradigm for demonstrating how fluctuation in being in people's physical state did not transmit. And what he did was develop a very simple experimental paradigm of getting genetically identical organisms, selecting them by differences in their phenocyte and hundreds and hundreds of times seeing what happened to them when you selected them. Even when they were genetically the same, you selected them, what happened to them when you bred from those extremes. And what you found, whether it was large beans, right the way through to studies done with fruit flies and rodents, none of this is transmissible. None of the thing which leads to people with the same genes being different transmits down. There's no major transmission of the shifts which occur that the environment causes or chance causes they do not transmit down the line. And this has been so well-studied, this is one of the most studied phenomena in biology. People stopped doing it in the 60s and 70s because they knew what the answer was going to be. In fact, it was used as a way of detecting very rare mutations because when something happened which went against this, some actual germline DNA mutation had occurred. And it's extraordinary that this has just been forgotten because when you get a new technology, you get a new word, everyone wants to jump on the bandwagon of the new technology, the new word. Even if you're a masseur, here you say, in the massage magazine, the integration of standard massage practices and the knowledge of the biology of adversity will change our minds, our physiology, our epigenetics, and hence our massage practice. So there you go, who cares about poor old Bill Hansen. So I'm going to show one bit of data. I thought I'd show one piece of data this evening. This is a recent study which looked at twins. Now, your birth weight, if you're a mum or a dad, relates to the birth weight of your offspring statistically. If you're a mum, it relates more strongly than if you're a dad because the interutory environment also has an influence. And then, so you look at the birth weight differences between twins, between identical twins, monazygotic twins are genetically identical, dizygotic twins are genetically 50%, they don't share 50% of the genes, just like any siblings. And you just look across the board, not looking within the pairs, just looking at these as people, and you show this, indeed, what this just shows is that the birth weight of the mum correlates with the birth weight of the offspring. And you then look between the twins, and in the dizygotic twins, where they have 50% of the genes are different, the birth weight of the mother relates to the birth weight of the offspring, the birth weight difference between the twin pair, the heavier twin, dizygotic twin has, on average, heavier offspring. You look between monazygotic twins who are genetically identical, and just like Johansson's peas, just like the peas they've regressed to the mean, the birth weight differences that exist between the monazygotic twins, which are chance fluctuations, blood flow goings differently in the placenta, something just happens, those are just not transmitted down. And as I say, this is some human data, but it's been shown so often that it's somewhat dull, but it's worth showing because all these data are just ignored. So, in my view, the great forgotten thing in nature versus nurture is the third component of variation. This is what has been most forgotten, and the third component of variation is stochasticity, is chance variation. Fluctuations at a molecular, right away from a molecular level, down to when you're actually looking at downstream things, also happening at the biographical level, if you like, but they start at the molecular level of just chance events which lead to differences. And as I say, this has just dropped out of the nature and nurture debate. These here are genetically identical crayfish. They're not the sort of crayfish you're going to eat, they're marbled crayfish, but they're genetically identical, created at exactly the same time, grown in exactly the same aquarium, and they end up very different sizes. Now, you know, imagine if you were trying to study them and trying to say, you know, what's led to one of these being sort of fat crayfish and a very skinny little stunted crayfish, it'd be impossible to identify these factors and they are just chance events. The great forgotten factor which contributes very importantly to differences are stochastic events. The thing which just falls out in the nature versus nurture debate and gives us space actually for the over promotion of one view or the other. So in my view, epigenetic mechanisms are extremely interesting. As I say, I spend my life now studying them. Extremely interesting because they actually integrate the environment. If the environment works through them, the smoking example I gave, I'm sorry I've reduced the environment to be a fag's. I don't eat green vegetables and stress, but you know, that's what the environment for epidemiologists is. Germline genetic variation. So if your genes influence your outcome and the environment influences the outcome, they will work through the same sort of processes. For developmental biologists, this is their bread and butter. There's a term in developmental biology called gene environment equivalence. It doesn't matter whether the gene expression, how the genes are expressed, is influenced by a genetic variant which leads to genetic difference or by the environment, the downstream consequences are the same. This incidentally, if anyone wants to be bored for half an hour over the drinks, this incidentally is why Mendelian mandemisation that Jane mentioned works, but I'm not going to explain my Mendelian mandemisation, don't worry. And also integrate stochastic events. There's been a very considerable study of how stochastic meleco-events influence the epigenome. This integration is a way of thinking how these come together. I mean, I think so, I really do think that it is beyond, in that sense, it's beyond nature versus nurture, it's nature, nurture chance and it's complex feedback loops through them. As I say, epigenetics is a confused epidemiologist friend. Recently I was giving a talk and I thought I'd look back to try and find out who was the first person who had been, in this hand-waving way, evoked epigenetics for something they didn't understand. I went through the major medical journals and searched on epidemiology and epigenetics and tragically what I came across was a paper by me in 1997. Talking about birth rate, which I've now just talked about. I said the actual resemblance in birth rate may be an attenuated reflection of the common factors, genetic, epigenetic, desperate, no idea what's going on or environmental, that lead to intergenerational similarity of birth rates. There you go. So I got into the BMJ, so there you go, it's worth British Medical Journal, so it's worth it. So, as I say, those mechanisms are not what's creating the excitement. And I think part of it is this notion that epigenetics is some sort of way out of a debate. Richard Lewontin, whose work I greatly respect and his book out just a few weeks ago, A Genetic Explanations, Sense and Nonsense, says something we're so used to reading now. We accept that organisms are material objects that ultimately owe their properties to their material natures, an error to suppose that the DNA sequence of an organism predicts its total nature and life history. The widespread general interest in DNA has seemingly validated the 19th century view that everything about us as individuals is specified in our biological ancestry. Now it's so that it's all in our DNA. But I actually think that this is a straw person sort of argument. You look back to the debates, one can come up with horror stories of eugenics, but you go back to the debates then and even then biologists, great biologists and anti-eugenicists Raymond Perle pointed out that just the genetic processes that we knew about together with chance and how biology worked just gave no determinism. He talked about this in terms of what for the eugenicists was most important, with sort of quality of person, intellectual quality. And he talked about how the superior people of the world, this is in 1927, have always been recruited from the masses intellectually speaking in far greater number than they have been reproduced by the classes by which he meant the posh vote. The almost infinite manifoldness of germ-plasmic combinations can be relied on, I think, to produce in the future as it has in the past, Shakespeare's, Lincoln's and Pasteur's, some socially and economically humble origins. And this is brilliantly prescient because what being able to sequence the genome and do genome-wide association studies where you just search for any genetic variant related to any trait has shown is that things like cognitive ability, huge numbers of genetic variants with tiny effects are what contribute to that. And of course they get shuffled, they are randomized when every germ cell is formed. And if there are genes of large effects, then they get selected out, they do not become common. So, together with the stochasticity which I talked about, this just sort of guarantees that we're virtually, you know, you're virtually just shaking a tumbler, dice tumbler with huge numbers of dice in it each time and why everyone is biologically individual and why variants and traits, the huge spread in traits is just maintained. So I think I'm willing to be like a Holstein or Brahman cattle or like yeast where there's no argument about missing, one slide left, there's no argument about missing heritability which you might hear tonight because there's much smaller ancestral population and you can demonstrate with the actual germline genetic data exactly the same heritabilities as you can demonstrate with, you know, other forms of estimating heritability. And I'd like to echo the anthropologist, sociologist, maybe philosopher when we're calling Bruno Latour, you know, who's wonderful book, 1919 book I think it was, we have never been modern. There's a critique of postmodernism on the grounds that one couldn't venture to discuss postmodernism because we'd never actually had modernity, we'd never actually arrived at a full understanding of what modernity was and what it offered. And I think that's the case with genomics. I think genomics, as we understand it, offers this extraordinary manifold, you know, summed up in the last words of Darwin's origin of the species. You know, there's grandeur in this view of life with its several powers having been originally breathed into a few forms or into one. And that whilst the planet has gone cycling on according to fixed law of gravity, the laws there from so simpler beginning, endless forms, most beautiful and most wonderful have been and are being evolved. And I think that the incredible complexity of the genomics and the chance and the environment without having to start discussing processes which in my view are oversold like some notion of Lamarck inheritance is enough to occupy a career. Thanks very much. Thank you very much to George. We're now going to move straight on to hear from Nicholas Rose and then there'll be some time at the end for a proper discussion and questions from the audience. So it's really my privilege to introduce Professor Nicholas Rose, who is one of the most eminent sociologists in Britain at the moment. He's Professor of Sociology and Head of the Department of Social Science, Health and Medicine at King's College London. And Nicholas Rose's work explores how scientific developments have changed conceptions of human identity and what the implications are of that at a societal level. So that's the sociological view, not just staying at the individual level but thinking about society. Professor Rose is also co-director of the Centre for Synthetic Biology and Innovation, a major research collaboration between King's and Imperial College London. And I was intrigued to see that Nicholas Rose was actually trained as a biologist as well as a psychologist and a sociologist. So he has that depth that interdisciplinarity brings. I first came across Nicholas Rose's work when I was doing my PhD and I read his book Governing the Soul back, that was sort of 1989 that was published, The Shaping of the Private Self. And that's widely recognised as one of the founding texts of understanding new ways of understanding links between expertise, subjectivity and political power. And Nicholas Rose's latest book is written in conjunction with Joelle Abbey Horashed and it's Neuro, The New Brain Sciences and the Management of the Mind. And that's published by Princeton University Press. So I'll give you a little book plug. Thank you, Jane. But over to Nicholas. Okay, well thanks very much to Jude and to Jane for the introduction. And to George for setting the scene. Now I've actually known George for about 30 years before he became famous, but he was still the same George. Now I don't entirely disagree with George but I think we need to avoid getting caught up in the either-or. Either we're seeing a revolution or nothing is happening. I think something is happening and it's not a revolution. And I also think it's necessary to separate clearly, I know George did this but perhaps he got a little bit lost at the end, two aspects of epigenetics. And the first aspect of epigenetics is how experience gets under the skin over a life course. And the second aspect of epigenetics which is the one that George spent most of his time criticising is the question of intergenerational transformation of those changes. I think they're separate and I think they're both interesting. What I want to do in my 20 minutes is first I'll just sketch and I'm sure many of you will be familiar the way in which this debate has taken shape and the way in which the antipathy between these two ideas of nature and nurture has come to dominate the relationship between the social sciences and the life sciences and perhaps also between progressives and conservatives. I want to suggest that there are changes in the life sciences and in the social sciences which allow the possibility of going beyond that. And then in the last part of my talk I want to say a little bit about one project which we're doing in my group at the moment which is about the age-old theme in sociology of mental life in the metropolis which is about how living in cities gets under the skin and that I think is a quite interesting example of the new opportunities for collaboration that are being opened up between the life sciences and the social sciences. Now you don't need me to point out to you that this question about whether human beings have a nature is one of the oldest questions in philosophy. And you also don't need me to point out that probably since about the 1970s many people began to argue that the life sciences, in particular developments in biology and developments in evolution, provided a clear scientific understanding of that relationship between nature and experience. And we see Edward O. Wilson's famous book on human nature, Desmond Morris, The Naked Ape, Stephen Pinker, The Blank Slater, a whole series of arguments saying that we need absolutely to understand what humans have inherited and the way in which that inherited constitution shapes their comportment in all sorts of really important ways. But what we need to recognise is that that separation between nature and nurture is actually a relatively recent one. And we also need to recognise that breaching it is not always progressive. So let's just take one moment to go before nature and nurture. When did nature and nurture become so separate? Well, they certainly weren't separate in the 19th century, in the European societies of the 19th century. In the European societies of the 19th century, an argument began to take shape which would have major implications for social and political debate and for practice across that 19th century. And the interesting thing about that argument was it made no separation between nature and nurture. Or rather, what it argued was that human beings are born with a certain kind of a constitution and that constitution can be weakened by the kinds of experiences that humans have over their lifetime. Indeed, people born with a weakened constitution which may be expressed in everything, insanity, tuberculosis, prostitution, alcoholism, religious further, that those people were likely to find themselves in life circumstances in corrupt milieu, especially moving into the cities, which would have an increasingly damaging effect upon their constitution. It would weaken their constitution by drink, by depravity, by masturbation, and they would pass that weakened constitution onto their children, and indeed in the case of the lower classes onto their many children, and that would produce a really vicious spiral of degeneracy, of degeneration. So we see here, I've just shown up on the board, Morrell's famous book on degeneration, which argued that almost every form of insanity or social problem was a manifestation of degeneration and picks wonderful history of the emergence and the spread of this idea of degeneracy across the 19th century. So we shouldn't think that blurring the boundary between what we're born with and what we experience is necessarily progressive. Okay, now we all know that the difference began to emerge, the separation of these two realms began to emerge in the late 19th century. It's conventional to associate this with the work of Francis Goulton who invented the term eugenics and who sought Darwin's cousin, as everybody always says, who made a clear separation in his argument between what was inherited and what was the effect of environment. Nature and nurture became the key terms from Goulton onwards. Nature is all that man brings himself into the world, nurture is every influence which affects him after his birth. Goulton, as we all know, the founder of eugenics and indeed it's that eugenic history that argument about the key importance of what is inherited rather than what's experienced which underpinned the huge hostility which one saw amongst all progressives and especially amongst social scientists that began to develop to those genetic arguments across the 20th and up through to the end of the 21st century. In particular, they focused around the question of the inheritance of IQ, the inheritance of aggression, the difference between men and women and so on. This I'm sure is familiar to all of you. One of the hate figures there, I've just put his book, Sociobiology, up on the slide there was Edward Wilson's book on sociobiology because he made the argument that what is true of ants and what is true of animals is also true of humans. This argument, this genetic argument, this genetic determinist argument really shaped the debate for about 40 or 50 years. And what one sees and you can see them along the bottom of that slide there is a whole series of attacks on what was taken to be all biological explanations of human conduct. They were all taken in one way or another to be either explicitly or implicitly repeating the sins of eugenics which are to condemn people on the basis of their inheritance to argue that differences between human beings are based on what they inherit, that aggression, that differences between men and women, et cetera, et cetera, are a product of inheritance and pretty much unchangeable by experience. You see the books of criticism across the bottom there. And I suppose the basic argument put most clearly at that point by someone like Stephen Jay Gould is to say, as he says in that slide there, we are, as Simone de Beauvoir says, le etre dans l'etre de netre pas, the being whose essence lies in having no essence or as it's put in that book, not in our genes, incidentally co-written by my dear and wise elder brother Stephen, biology, human biology has freed humans from their biology. The very nature of human biology is to have no nature. Now I think what we're seeing and epigenetics is part of this are changes in both the social sciences and in the life sciences which allow us or provide the basis of us freeing ourselves from this antagonism. Beginning to recognise that biological explanations of human affairs do not inescapably have this determinist form and beginning to recognise that there is nothing inherently problematic, anti-progressive, anti-transformative in recognising that human beings are, after all, animals. Particular types of animals, it's true, but animals. On the one side of the screen, with the red border, I put some of the transformations that are emerging within biology. In the book, Jay mentioned most recent book I wrote neuro, in a previous book that I wrote called The Politics of Life itself, I argued that we were seeing a fundamental transformation in the life sciences away from the idea that the more biological something was, the more determinist it was, biology as destiny, biology as fatalism, to a different argument, absolutely associated with developments in molecular biology, with the beginning of the understanding of the human body and the human organism as not mystery but mechanism, the argument that the more biological something was, the more open to transformation it was. Society was incredibly difficult to transform, but if we understood the human organism as machine, we could, in a sense, reverse engineer that machine, we could intervene in it, we could transform it at that level, whether it's gene therapy, whether it's the claims about the rise of new smart drugs, whether it's assisted reproductive technology transforming fundamentally the capacities of human beings of women to reproduce, the idea that the more we knew about our biology, the more we could do about it, I think brought about a really significant, if you'd like, not just an epistemological change, not just a change in the nature in how we understood ourselves as beings, but also a kind of ethical change in our relationship to biology. You see the same thing developing in genetics. Some of you may remember that when the sequencing of the human genome was undertaken, there was the view that humans had something like 100,000 genes and that each gene encoded every single characteristic. As a result of the human genome being sequence, one of the wonderful things about science that George and I would probably agree with, we now realise that human beings have about 20,000 coding sequences. There is clearly not one coding sequence for each human function or each human protein. So something is going on between the sequence of the DNA and the reading of that sequence and it's transforming into enzymes and into proteins and it's in that something going on that we need to try and understand how organisms, not just human organisms, but other organisms are shaped over the course of their development. Epigenetics, which I think the most fundamental thing about epigenetics is not the intergenerational transition argument, but is the beginnings of a clearer understanding of how experience from the moment of conception and even before gets under the skin and shapes human beings in a most fundamental way, body and brain, and I'll say a little bit about that in a moment. Jane mentioned I was originally trained, that's probably a rather exaggeration, I started off my university career as a biologist, actually at Sussex University in 1965, in the department whose head was John Maynard Smith, a wonderful fruit fly geneticist, a wonderful geneticist, but to the extent that I was a biologist, I was a developmental biologist and developmental biologists even back in the 1960s argued that what was crucial in development was not so much the DNA that you inherited, but how that was transformed second by second, minute by minute, year by year, et cetera, et cetera, over your life course from the very moment of the fertilisation of that cell. That's what leads the same DNA to differentiate into livers, into leukocytes, into limbs and so on and so forth. So if you're a developmentalist, this temporality, this time scale of development and the way in which that works at the genetic level and at the level of the organ and at the level of the organism, always in dynamic interaction with its environment, whether that's the environment outside the cell, whether that's the environment in the body, whether that's the environment outside the body, that becomes key to understanding. But I don't actually think in this transition it is simply epigenetics. We're seeing other arguments, which I'll say a little bit about in a second, about neuroplasticity, in particular about how the brain, far from being a fixed organ, is perhaps the most open and modulatable organ of any organ in the body, constantly in transaction with its environment, which is shaping it at the level of its synapses, but also at the level of its structural and functional organisation. We see arguments about neurogenesis, that is to say the production of new nerve cells in response to environmental inputs. We also see arguments which kind of lead us to believe that us humans and other organisms are not so self-enclosed by the magical boundary of the skin, as we've always thought. We're inhabited by millions, hundreds of millions of little microorganisms in our microbiome, so we are transformed by the things that inhabit us with it from within. There was a famous division in the 19th century, probably most clearly elaborated by Claude Bernard, between the miliar interior and the miliar exterior. The barrier, the boundary between what went on within the body, which was a self-regulating system enclosed by the skin, and everything that happened outside that could only get in through the skin. Now, there are many arguments that that division was fundamental to establishing our modern understanding of biology, but I think we're now seeing a blurring of that boundary. That boundary is so much more permeable than we've ever seen before. At the same time, on the other side of this dichotomy, hesitantly and probably over-speculatively and probably over-exaggerated, we're beginning to see a recognition in the social sciences that it's not so horrible to place the human among the animal. That we are animals, that some crucial features of our existence are shaped in the same way as of our primate cousins, and that beginning to understand our animal nature and indeed placing ourselves in a world of animals or other organisms is not only cognitively correct, but it's also ethically correct because it recognises our interaction with the world outside. Under the skin. So how do things get under the skin? Unfortunately, if you Google under the skin these days, you find that movie, which I haven't seen, but I have read the book by Michael Faber, and there indeed is Scarlett Johansson as an alien who's come... Well, I won't spoil it for those of you who haven't read it, but there's a different sense in which this phrase, how adversity gets under our skin, has become a slogan, perhaps an over-simple slogan, but at least one which begins to break down that barrier between what's outside and what's inside. The picture here, which I'm going to say a little bit more about these mice in a moment because that, I think, has a little bit to do with George. This is an article by Steve Hyman, former director of the National Institute of Mental Health, then Provost of Harvard, and now the director of the Broad Centre in the United States, beginning to argue exactly how adversity, in this case adversity for small rodents, shapes the very nature of the biology of that rodent. And indeed, contra Professor Davies Smith here, does shape the way in which that rodent deals with that rodent's pups, does shape the way in which those pups in their turn deal with their pups, and does shape the way in which their pups in their turn deal with their pups. That's a kind of transgenerational inheritance of experience, which is interesting and perhaps a little bit problematic. So, we're not just talking here about epigenetics. Perhaps the place where I first came across these arguments was in the increasing emphasis on gene environment interactions, especially in psychiatry. There was a study by Caspian Moffitt, based on another cohort study, actually, which showed that children who were subject to adversity in their childhood did not necessarily grow up to be maladjusted or indeed to go on to having other sorts of problems. They only manifested those problems in their adolescence and in their adulthood if they possessed a particular variant of one gene. This particular gene, the serotonin transporter gene, came in two varieties. They made a very simple division between long and short varieties of this allele, and they showed that individuals who had two short alleles on the promoter region of the serotonin transporter gene and were subject to maltreatment and abuse in their childhood went on to have significant problems in adolescence and adulthood. Those who did not have that variant did not go on to have those problems. So, the gene did not produce the problems. In fact, what produced the problems, and this is the way in which they transformed the idea, was the environment. The environment produces the problems by acting upon a particular genomic makeup. So, the first breach of that belief that it is the gene that is determinant here. The second, epigenetics. Now, epigenetics, I won't say anything very much about epigenetics, but I just want to quote one particular bit of research which maybe George will say a little bit more about in the moment. And this is the research by Mike Meany's group, he's up there, and Ziff's group. This is the research which I think does indicate something about transgenerational transmission. This is research done with rodents, with guinea pigs, or with rats. If you so organise your experiment so that some of your guinea pigs or rats give a lot of grooming behaviour to their pups, and others give a little bit of grooming behaviour to their pups, and then you see what happens to those pups in their turn when they grow up and how they treat their pups, where their pups grow up and in their turn treat their pups, you can begin to see intergenerational transmission of these forms of grooming behaviour. Ziff and Mike Meany and others argue that this is epigenetic transmission across the generations. Of course, it's not exactly clear how that works, and there is indeed quite a lot of hand waving going on. And even if it was the case, it's not necessarily tremendously good news. Tremendously good news that how a mother, in this case a mother, guinea pig, treats her pups, in this case a puppy, a guinea pig, has an influence on that pup's behaviour and then on that pup's children's behaviour, et cetera, down all the generations. It's not so progressive, it can indeed just be another form of eye-blaying the mother. The other things which you begin to see, and since I've been given the five minutes here, I won't say very much about this, are arguments that demonstrate, evidence that demonstrate just how plastic the brain is in response to environmental inputs. For instance, we know that individuals who suffered very severe strokes can regain quite a lot of function by what's called cortical remapping. There's a great deal of redundancy in neural systems, and that redundancy can be activated, and that activation is something that can be generated by systematic programmes of training. So this leads to the belief that actually what goes on in your brain, and in particular both the structure and the function of your brain, can be deeply affected by the kinds of environment that you're in. Of course there's an awful lot of hoo-ha and gaff about that, re-wire your brain for this, re-wire your brain for love, re-wire your brain for success, but behind all that I think there's something rather interesting which does seem to begin to identify a mechanism by which experience such as stress does get in and fundamentally shape neural pathways. This is the most interesting recent research, this is, well there's quite a lot of this research, some of it quoted in the most unreliable Guardian, I know, by Andreas Meier-Lindenburg's group. Andreas Meier-Lindenburg's group argue that city experience shapes the way in which individuals process stress. Let me just break that down a little bit. If you're born in an urban environment and subject to stress as you grow up, then when you're subject to stress as an adult, you'll process that stress very differently than if you're born in a rural environment. Indeed, if you're just brought up in an urban environment, whether or not you're born there, you develop different kinds of stress processing mechanisms. Stress of course is a very all-purpose kind of explanatory thing, what is stress, we don't really know, it's stressful to be in employment but then it's stressful to be unemployed, stressful to be single but then it's stressful to be married. The way in which these environmental phenomena are described is very, very variable. Nonetheless, Meier-Lindenburg and his group seem to be able to show that experience of stress at an early age affects the way in which your brain processes stress when you're an adult and as you'll see by these ubiquitous pictures of the bits of the brain quotes, lighting up, different areas of the brain are activated in stress processing in those who've been born in cities or those who've been born outside the cities. Stress and the city. So, just to conclude, I think something interesting is happening here. It's not so much about the intergenerational transmission but it is beginning to understand in new ways how the boundary between what's inside the body and what's outside the body is much more permeable than we've believed before. How experience from the moment of conception onwards shapes the human body and the human brain in rather fundamental ways that experience gets under the skin and that if, as social scientists have tried to do forever, certainly since the late 19th century, if we're trying to understand the way in which social suffering, social disadvantage, mental disorders and so on are distributed across a population and their differential effects across that population, we begin to see how social scientists and life scientists need to collaborate together in order to understand those phenomena. Are mechanisms important? Social scientists have traced out in very great detail the distribution of pathologies of mental disorders across urban space. But I think it's quite important not to see them as just distributed across urban space but to begin to understand the mechanisms by which those forms of social disadvantage of racism, of exclusion, of living in the kinds of environments here, which I've just shown on this slide from Mumbai, how they do shape us at some fundamental biological level. A year ago, there was an editorial in Nature that argued that it was time for social scientists and life scientists to kind of bury the hatchet, that in fact the social scientists had demonstrated very clearly what the life scientists were now trying to identify at the level of mechanism. More or less the same time, I published a little paper called The Human Sciences in a Biological Age, which argued that one should try and develop a new relationship between the life sciences and the social sciences. I think there are many dangers. I think we have to do this slowly. I think we have to avoid the kind of overhyping that is easy to parody but brings the serious research into disrepute. But I do think there is an opportunity for serious collaborative research, which is, as we are told, beyond nature and nurture. Thank you. So thank you very much to Nicholas and George for two very thought provoking presentations, very vivid images. I'm just going to start off with one or two brief questions and then turn it over to the floor. And what I'll do is collect two or three questions from the floor at once and pose them to both Nicholas and George so that we get a good debate going. And it seems to me that you were both sort of in summing up saying that a lot of the recent work on epigenetics has been rather overhyped and that what's important here is understanding more about permeability between the environment and human biology. So you both seem to be almost quite unified on what's important is understanding the mechanisms of how things get under the skin. There seem to be a little bit of difference and I'd quite like to ask George to just respond to the examples that Nicholas was giving about the pups and the grooming of pups and whether that does actually challenge your remarks that it's overhyped the intergenerational transmission. And then I'd like both of you as well just to reflect on in five or 10 years' time if we have a really productive relationship between the life sciences and the life in the social sciences what we might expect to see. So a very sort of optimistic view of intergenerational interdisciplinary research. So George first would you like to just respond to the pups question? So there are very different things talking about transgenerational facts where you're just saying that one sees things going down generations. I mean income goes down generations and it's not necessarily that if you happen to be lucky enough to be Alan Sugar's son that something is methylated which means you become very rich it's more likely that you get his money. So very clearly many processes are transmitted and behavioural processes and social processes. These things all clearly go down the generations. The question is a very specific question about epigenetic inheritance and epigenetic inheritance is when a trait something which influences a particular trait like something influences body mass index changes the body mass index of the parent and that that is then transmitted down the generations. So that is the domain of epigenetic inheritance. That is the domain which is where things are very poorly demonstrated. There's reasons to believe that even effects exist they are tiny compared to other things which influence why parents and offspring are alike and one can go into lots of detail about that. I don't find the Michael Meany type work at all challenging because I find it very exciting because one is looking at how behavioural patterns are transmitted and then also looking at how at each generation they reproduce each other and in fact we work closely with Mike apart from me he was just foolish enough to put me on a grant which then of course didn't get funded to actually do some of this sort of work in our cohort with him. So I think that what I was talking about was a very specific aspect of epigenetic inheritance which is how things which are acquired transmit down through the same outcomes. Which is that? I think we agree about this. I mean I think the mechanisms by which this maternal grooming of the path goes down the generations are not the kind of epigenetic inheritance that George is critical of. That would mean there was a permanent transformation of the genome in some way. Maybe just through its methylation marks but maybe of the genome itself and that that was what was passed down through the germ line and that was what was inherited by the next generation. And I don't think there is any evidence from the Mike Meany work that that is how the intergenerational transformation works. There are methylation patterns. They do shape the behaviour of the pup. They then shape the behaviour of the pup towards its pups which shape the methylation profile of those pups, et cetera, et cetera, et cetera. So when it's talking about a movement down the generation but it doesn't violate the principle that George I think is quite correctly making clear. Sorry, I interrupted you, George. No, that's fine, I think. We agreed about it. We're even collaborating on something. And that's why when this is glossed as you know why everything you've heard about evolution is wrong then that is moving well beyond what's been demonstrated. OK, so perhaps I can ask you at the end to comment on the, you know, in 5, 10 years' time being optimistic what would truly interdisciplinary research yield for us. And perhaps we can turn now to the audience for some questions or comments. And I can see we've got a roving Mike. So do wait if you've got a question you'd like to put. Yes, in the front. You said that, I mean, for what you've said is very hopeful. But the thing is if there are two in terms of the brain, the effects of the environment in the brain, but if there are two variants of serotonin then it's not so hopeful. OK, so there's a question there about how hopeful this is. Are there any other questions to collect up? I was interested in Europe, sorry. I was interested in what we heard about neurogenesis and this idea of systematic retraining of organisms. And I just wonder whether either the speaker could comment on the role of psychotherapy and psychiatry in relation to systemic retraining. Thank you. OK, and one more question over here. Thank you. I was interested in what you said, Professor Rose, about the life sciences shifting away from determinism alone and sort of seeing the more biological you can comprise something the more you can see it as a machine, the more you might be able to intervene with it. And in my own work as a sociologist working in the HIV field, I'm seeing this very much as I think I would reframe it slightly differently and talk about exhaustion among hard scientists, perhaps in a range of fields who are needing new materials to kind of work with and to the same extent actually exhaustion for people who are working at things on a social side who are becoming more biomedicalized. So in a lot of the conferences I go to, I'm seeing social scientists talking much more about biomedical solutions to HIV and I'm seeing clinicians being far more interested in talking about austerity and socioeconomic. So perhaps it isn't necessarily that we're embracing one another's worlds, but that we're looking for new explanations out of exhaustion. So three rather different and challenging questions. Nicholas. All right, I'll just take them in order. Serotonin, OK, so just to back off a little bit. Serotonin is a neurotransmitter. We have hundreds of neurotransmitters. The suggestion is that these neurotransmitters come in various levels of activity, but some of them are more active and some of them are less active. That if individuals have some combinations of these different neurotransmitters in less active forms and they suffer various kinds of insult, environmental insult or physical abuse, that is going to generate problems for them. But if they don't have, though, if they have different forms of those neurotransmitters, the environmental abuse is not going to have the same consequence. So these are very simplistic explanations at the moment. Two forms of serotonin, two forms of monowhewy and oxidase A, et cetera, et cetera, et cetera. But I think what they are trying to do in a very hesitant way is to transform the way in which we understand the relationship between our genes and our environment. To argue that there are much more complicated ways in which environmental effects work on multitude of variations amongst the genes in order to shape our vulnerability, our susceptibility or indeed our resilience to various kinds of life events. And the interesting thing about those and the Caspia Moffitt slide, which I showed very briefly there, is that the argument is that the pathogenic effects are in the environment and whether they have an effect on the individual depends upon their genetic makeup, but the causal direction, if you like, is being inverted. It's not that the genes express themselves, it's that the environmental insults have effects dependent upon a person's genomic makeup. Perhaps there's nothing so radical about that. But in the area where I've been working, which is in the area of psychiatric disorders, which is the area where the Caspia Moffitt study, which was a big study, a cohort study based on a cohort of families in Dunedin in New Zealand, in the area where I was working, this transformation of our understanding of the relationship between gene and environment was very significant. Second, neurogenesis and systematic retraining of the organism. We need to kind of separate them out slightly. So the work by Paul Bakurita and others began to show that individual, they did this work, some of this work was done rather controversially on animals, and actually some of this work led to the beginnings of the anti-vivisection campaigns and so on and so forth. But it began to show that humans who'd had a lesion through a stroke or animals where you could give an artificial lesion or you could constrain the animal in certain ways, that different areas of the brain would take over those functions and that this retraining, quote rewiring of the brain could be intensified by systematic training and turned into training programmes. So it began to show again the way in which even structural issues in the brain were very amenable to environmental, not very amenable. We can again over-hype this, and I slap myself on the wrist every time I over-hype it, but something interesting. The neurogenesis argument just very, very quickly. So there was always a belief that in complicated mammals like humans, especially in the human brain, that the nerve cells that you had developed, the neurons that you had developed through gestation and in the very early years were all the neurons that you had. From that time onwards, it was downhill all the way. Every cigarette, every glass of wine, every other insult to the brain would lead to the death of neurons. And there were very good arguments as to why it was thought that there could be no neurogenesis, that's birth of new neurons, in the adult human, in the very complex adult human brain. And in a series of really elegant experiments, and very persistent experiments over many years, Elizabeth Gould and her colleagues demonstrated that even in the adult human brain new neurons could be formed, hooray. But the other thing that she began to argue was that the death of neurons and the birth of neurons, both of those things were understandable in terms of environmental effects. Certain environmental effects led to more rapid death of neurons and certain forms of environmental stimulation led to more rapid growth of neurons. This argument about neurogenesis is quite interesting. Many people who still believe that some psychiatric drugs work, which is an open question, believe that drugs like Prozac, et cetera, selective serotonin reuptake inhibitors, work by neurogenesis, not by working on the amount of serotonin in the synapse. Are we exhausted? It's all to the good if we're finding new explanations. We have to be a little bit wary, I'm a little bit wary of all the social scientists leaping on the life sciences bandwagon. That's where the money is. We know that the life scientists get 10 times as much money, 100 times as much money as us social scientists. That's where people are prepared to put their investment. That's where the leading edge is supposed to be. Social scientists are not averse to seeing where the trough is and beginning to direct their snouts in that direction. We have to distinguish between people that are just moving there because that's where the money is and that's where the fashion is. And people who are beginning the slow and very difficult work of developing collaborative relationships with the life scientists, which are infused by differences of power, differences of money, differences of status, et cetera, et cetera, et cetera. Social scientists should not want to be the handmaidens of the life scientists. But it's a difficult relationship. George, have you got... I'll just speak very briefly to one of the issues which is the gene-environment interaction issue. I mean, I think the issue with gene-environment interactions is that with very traumatic gene-environment interactions with common genetic variants, then you have the same issue in terms of why of these things existed against purifying selection, against the fact that they would have fitness advantages or disadvantages. And so what one finds is that they are very well established dramatic gene-environment interactions and they are with evolutionary novel exposures. So, for example, with alcohol, which is a relatively evolutionary novel exposures, there are people in East Asian countries who have variants which simply cannot have clear the toxic product who, if they do drink, get sick, we get headaches, palpitations, all the nasty things from alcohol and then get esophageal cancer like 30 times, 40 times the rate of other people with cigarette smoke and the reasonably large gene-environment interactions with drugs, which are evolutionary novel. When I was practicing as a doctor, you would get worried about using gentamicin because some people weren't deaf and there's a particular mitochondrial variant which accounts for most of that. Very good antibiotic, which can now be used if you test people with flu-coxacillin. People's livers used to melt away. There's very small percentage of people but their livers would melt away and there's a single genetic variant related to that. Now, so that those are evolutionary novel exposures but for things which like stress, which are in a stress in a generic way, which are not evolutionary novel, it is unlikely in a way that one would get very substantial interactions and the Caspian Moffit studies are actually, in my field, they're pin-ups of poorly done studies which absolutely fail to replicate. When people try these things in larger studies, they have simply not replicated. And the bizarre findings that they have for each of their studies is that they have no genetic main effect. So they get this perfect crossover. So you have children who are treated badly and they have one genetic variant and then they're likely to get higher rates of the nasty outcome. What's forgotten about, and then in the discussion of that paper, they actually said one could test people genetically and find out people who you have to abort and not be nasty to. Because they get no genetic main effect, the only way that happens is because they get a perfectly balanced effect. The people with the other genetic variant do better if you treat them badly. The equal conclusion of their studies is actually genocyte people and if your kid has the short arm then you've got to be nasty to them, otherwise they're more likely to get depressed. So it's quite lucky that those haven't replicated because they don't have a fantastic policy implications. There's reasons why the substantial gene-informed interactions that have been detected have been with evolutionary novel exposures. That doesn't mean that gene-informed interactions don't exist. Of course they absolutely exist and epistatic effects, i.e. gene-gene interactions exist, but they're relatively small effect. They're going to be a myriad of small effects and you've got to remember that with the shuffling of genotypes and the kind of experience that every organism is a unique organism, which means that they cannot be disciplined. They go into that part of the explanation of difference, which might as well as be called chance. So I'm not greatly optimistic about detection of very substantial gene-informed interactions with common exposures and common genetic variants and I think there's good evolutionary theory for why that's the case. Thank you very much. You can see the difference is that I'm trying rather optimistically to identify some areas where I think there are interesting lines of development that we can explore. I think George's Cautions are absolutely right. We could argue about Caspian Moffit, which I don't want to do now, but I think one should not ignore these five or six different areas, which I've tried to highlight, where something interesting seems to me is beginning to happen. So I'd like to open it up to the floor again if there are another couple of questions that people wanted to pose. Yes, gentlemen, at the back. Yes, Dan. It was a mention of Alan Sugar. I wondered what the take-home message for Alan Sugar should be. And that relates to Raymond Pearl identifying Shakespeare, Pasteur and Lincoln as coming out of the masses, and presumably their offspring disappearing back into the masses again. All think of Bill and Melinda Gates, for instance. Is the take-home message for the very rich that within two or three or four generations anything that will happen to be special about them will be gone, so passing on the money is much more important if they're selfish? Or is there a more optimistic message for the very rich than this? That's an excellent final question, so let's... So I think that's an interesting question. I think that speaks to why the very rich should be Rawlsians. They should think of themselves into a situation where they are in the ideal speech situation without knowledge of what's going to happen in the future, because the fact that most of what actually happens is just chance means that what you actually want to be in is a situation where there is reasonable equality of opportunity, because down the line, exactly your descendants are likely to might well be in the situation of requiring those opportunities. So when I've been writing on this notion about how important chance is in terms of influencing variation, which is not something which scientists in many areas embrace because putting in a grant application to say, well, I'm going to study stochasticity, I'm going to find the causes of chance isn't that likely to get funded. It's actually a wonderfully democratising notion, because it actually does mean that whatever one's level of privilege, then some form of nodding to the Rawlsian position is the appropriate one to take. I mean, just not a word on Alan Sugar, but I think chance is important, stochastic variations are important, et cetera, et cetera. But anybody who's traced the lineage of power, influence, and money down all the generations over the last 200 or 300 years would suggest that some things do stick from generation to generation. I suspect that they have almost nothing to do with biological inheritance, but a lot to do with all sorts of other things that social scientists have investigated very clearly. And I do think just putting this the other way around, that we also see that social disadvantage passes down the generations. We also see that life expectancy of those who live in different areas of our cities is very different. We see that the psychiatric disorders that they are afflicted by are very different, and that those also pass down the generations. These have been charted extremely well by social scientists. And when that editorial in Nature was published, what the editors of Nature argued was that social scientists have traced these lineages of advantage and disadvantage, and indeed their research about the passage of these down the generations has been well-vindicated. And what we now need to do is to understand much more clearly the mechanisms. And this is my 15 or 20-year on a sort of scenario, because especially if we think about urban experience, more than half the inhabitants of our globe now live in cities, although they live in cities of very different sorts, whether they're Mumbai, whether they're Buenos Aires, whether they're Rio, whether they're Paris, they live in urban environments. Those urban environments are full of everything from toxins, biological toxins to social and political toxins. These, it seemed to me, stunt the lives and shape the lives of many of our fellow citizens in ways that are quite difficult for them to overcome, however much they might exert themselves, however much some succeed in the ghettos because of their resilience, many others don't. And myself, I think that some of these mechanisms that may be gestured out a bit too loosely help us understand this, and if they help us understand it, given my optimistic view of things being easier to change if they're biological than if they're social, they may just help us to understand how we can counter them. That's my optimistic view anyhow. Thank you, well let's leave it on that optimistic note and the optimistic thought of an evolutionary novel experience which is having a drink at the end of the evening. Good description of alcohol. So just to finish with that, I'd very much like to thank Jude and her team for putting on this very interesting event and just to hand over to Jude to tell us about any forthcoming events. In November, we're hoping to be starting our new series in conjunction with the Academy of Social Sciences. This is carrying on from our Myths and Realities series that we had that finished last year and we're going to be calling this one Enduring Ideas. At the moment our plan is, although it may change, to start in November with democracy because we think there's quite a lot of democracy about to come up with the May local elections, European elections, the Scottish referendum and of course in a year's time, just over a year's time, the general election. So we'd be doing a new series called Enduring Ideas so keep a look out for that. And then Alan Sudlow is here somewhere, he was here somewhere, there he is. We'll have information about any of the other beautiful science linked events going on. I think there's one on Friday on the joy of sleep or the power of sleep. So that's in the conference centre. So if you have a look on our website and what's on. So thanks very much and thank you all for coming and the bar is now open.