0:00:03.329,0:00:07.664 We are on the brink of uncovering a hidden world. 0:00:07.829,0:00:14.780 A world that connects past and future generations in ways we never imagined possible. 0:00:14.810,0:00:15.639 What this means is 0:00:15.639,0:00:23.017 an environmental exposure that your grandmother had could cause a disease in you - 0:00:23.017,0:00:25.801 even though you've never been exposed to the toxin - 0:00:25.801,0:00:29.272 and you are going to pass it on to your great-grandkids. 0:00:29.272,0:00:35.374 These extraordinary discoveries have the potential to affect every aspect of our lives. 0:00:35.374,0:00:40.704 It's not just the genes, but also the environment in the early life of your ancestors. 0:00:40.704,0:00:44.402 It's not so much "you are what you eat," 0:00:44.402,0:00:48.363 it's that you are what your mother ate, and maybe you are what your grandmother ate. 0:00:48.363,0:00:54.460 And if you take our data, you are what stress your grandmother or grandfather had. 0:00:54.460,0:01:00.916 It will change the way we think about our relationship with every generation. 0:01:02.317,0:01:06.776 It makes me feel closer to my children. 0:01:06.776,0:01:10.129 What I experience, in terms of environment, 0:01:10.129,0:01:16.071 will have some type of a legacy in my children and my grandchildren. 0:01:16.133,0:01:20.325 The science of inheritance is being turned on its head. 0:01:20.417,0:01:25.206 We're changing the view of what inheritance is. 0:01:58.169,0:02:04.787 This small Swedish town may hold the evidence to launch a medical revolution. 0:02:04.787,0:02:10.042 Overkalix lies huddled on the edge of the Arctic Circle. 0:02:11.058,0:02:18.543 Inaccessible and remote, it was cut off from the rest of the world for most of its history. 0:02:19.158,0:02:25.406 Marcus Pembrey has traveled here to meet his colleague Olov Bygren. 0:02:26.697,0:02:29.970 They believe that the story lying buried in these graveyards 0:02:30.185,0:02:34.486 may hold the proof to their radical ideas. 0:02:38.640,0:02:42.384 This group of people could contribute to ... 0:02:42.384,0:02:46.343 really a sea change in the way we think about inheritance. 0:02:46.343,0:02:53.671 They have come to this churchyard to find grandmothers and granddaughters, grandfathers and grandsons. 0:02:53.671,0:03:00.235 Connecting people who lived almost a hundred years apart in entirely new ways. 0:03:00.235,0:03:04.888 Uncovering links that confound scientific thinking. 0:03:05.580,0:03:10.450 Up 'til now, inheritance is just the genes; the DNA sequence. 0:03:10.450,0:03:15.222 I suspect that we are going to be able to demonstrate that the inheritance is more than that. 0:03:18.852,0:03:22.420 It is the culmination of more than twenty years' work. 0:03:24.423,0:03:29.877 And for the first time, Pembrey is confronting the magnitude of their discovery. 0:03:29.892,0:03:34.540 It really has come alive for me - coming here - more than I had expected. 0:03:34.540,0:03:39.961 It re... I'm really quite sort of emotional about it. Wonderful! 0:03:45.096,0:03:50.192 Marcus Pembrey is one of a select band of scientists. 0:03:51.207,0:03:56.415 A band of scientists who are daring to challenge an orthodoxy. 0:03:56.415,0:04:06.045 They believe the lives of our parents, grandparents, and even our great-grandparents can directly affect our well-being, 0:04:06.076,0:04:11.059 despite never experiencing any of these things ourselves. 0:04:11.181,0:04:16.703 To many, these ideas are regarded as scientific heresy. 0:04:18.098,0:04:22.462 You cannot predict where discoveries will be. 0:04:22.462,0:04:26.059 The only thing you can do is to follow your instinct. 0:04:28.045,0:04:36.724 Conventional biology has always believed that our genetic inheritance is set in stone at the moment of our conception. 0:04:36.755,0:04:43.049 At that instant we each receive a set of chromosomes from both our mother and father. 0:04:43.049,0:04:50.993 Within these chromosomes are the genes: strips of coded DNA, the basic unit of inheritance. 0:04:51.639,0:04:57.688 After conception it was assumed that our genes are locked away inside every cell of the body, 0:04:57.688,0:05:01.405 protected and untouched by the way you live. 0:05:01.405,0:05:10.759 So, what you do in your life may affect you, but your genes remain untainted, unchanged for future generations. 0:05:11.621,0:05:17.590 In classic genetics, your parents and grandparents simply pass on their genes. 0:05:17.590,0:05:22.468 The experiences they accumulate in a lifetime are never inherited - 0:05:22.468,0:05:29.690 - lost forever as the genes pass untouched through generation after generation. 0:05:32.602,0:05:37.846 The biology of inheritance was a reassuringly pure process, 0:05:37.846,0:05:43.404 or so it seemed. 0:05:43.404,0:05:52.184 In the early 80's, Marcus Pembrey headed the clinical genetics department at Great Ormond Street Hospital for Children. 0:05:52.184,0:05:58.453 He was frequently treating families with unusual genetic conditions. 0:05:58.453,0:06:02.703 We were constantly coming across families which didn't fit the rules, 0:06:02.703,0:06:07.597 didn't fit any of the patterns that genetics were supposed to fit. 0:06:07.597,0:06:13.181 So you think of chromosome abnormalities and you check the chromosomes and they're normal, 0:06:13.181,0:06:20.480 so you then have to start imagining - as it were - you know, what might be underlying this. 0:06:20.480,0:06:26.260 And you were really driven to try and work it out because the families needed some help. 0:06:26.260,0:06:32.182 The more families he saw, the more the rules of inheritance appeared to break down. 0:06:32.182,0:06:38.519 Diseases and conditions that simply didn't fit with the textbook conventions. 0:06:38.534,0:06:44.049 One condition in particular caught his eye: Angelman's syndrome. 0:06:44.049,0:06:49.984 Named after Harry Angelman, the pediatrician who first described Angelman's syndrome. 0:06:49.984,0:06:56.535 He referred to them as "Happy Puppet" children, because it described to some extent the features. 0:06:56.535,0:07:02.015 They have a rather jerky sort of movement when they're walking. 0:07:02.046,0:07:08.348 These children have no speech, they are severely incapacitated in terms of learning, 0:07:08.348,0:07:14.737 but are uncharacteristically happy, and they're smiling all the time. 0:07:17.290,0:07:27.094 The condition was caused by a genetic fault: a key sequence of DNA was missing, deleted from chromosome fifteen. 0:07:27.710,0:07:29.831 Then we came across a paradox. 0:07:30.017,0:07:36.107 At the same time, the same change - the same little deletion from chromosome fifteen - 0:07:36.107,0:07:47.286 - had been clearly associated with a quite different syndrome much milder in terms of intellectual impairment: the Prader-Willi syndrome. 0:07:49.271,0:07:54.015 These children are characterized by being very floppy at birth, 0:07:54.015,0:08:03.172 but once they started eating properly and so on, they then had an insatiable appetite and would get very, very large.[br] 0:08:03.172,0:08:06.400 What Pembrey saw simply made no sense. 0:08:06.400,0:08:09.167 Here were two completely different diseases - 0:08:09.167,0:08:17.804 - Angelman's syndrome and Prader-Willi syndrome - being caused by exactly the same genetic fault. 0:08:17.804,0:08:20.340 So here we had a very bizarre situation, really. 0:08:20.340,0:08:27.820 How could anyone propose that the same deletion could cause a different syndrome? 0:08:28.359,0:08:34.228 It appeared to Pembrey as if the simple view of inheritance was beginning to unravel. 0:08:35.536,0:08:41.183 But his doubts were contrary to the tide of optimism sweeping the scientific community. 0:08:44.383,0:08:51.563 In the early 1990's, the biggest project ever undertaken in biology was captivating the world. 0:08:51.563,0:08:58.365 The Human Genome Project will be seen as the outstanding achievement in the history of mankind. 0:08:58.365,0:09:05.842 The Human Genome Project was to be the pinnacle of a century of work on genes and genetics. 0:09:05.888,0:09:10.855 It seemed as if the secrets of life were at our fingertips. 0:09:12.178,0:09:13.894 The genetic blueprint of mankind. 0:09:13.894,0:09:16.446 Mapping out maybe the whole human genetic code. 0:09:16.446,0:09:20.459 It's a set of instructions to make a human being. 0:09:20.920,0:09:25.346 The human genome is like a bible where everything was written down. 0:09:25.346,0:09:32.459 The hope and the expectation was that once we had that book in front of us - and all the letters - 0:09:32.459,0:09:39.877 - we could just read down the pages and we would understand how the body was put together. 0:09:39.877,0:09:44.686 It would offer a complete understanding of human biology at the molecular level. 0:09:45.471,0:09:53.296 The hope was that once the code was written down, scientists could find the genetic cause and cure for every disease. 0:09:55.465,0:10:01.239 ... could lead to the end of diseases like cancer, Parkinson's, Alzheimer's, diabetes ... the list is endless. 0:10:01.239,0:10:06.172 We were thinking of genes in a very mechanical way. 0:10:06.172,0:10:09.407 We were thinking of them just in terms of the sequence of the letters. 0:10:09.407,0:10:13.119 We were all working out how we could work out what all the letters were in the book. 0:10:13.935,0:10:21.099 Scientists estimated that the human genome - the book of life - would contain around a hundred thousand genes. 0:10:23.160,0:10:27.065 And then when they started sequencing, they realized that maybe a hundred thousand genes, 0:10:27.065,0:10:29.800 then it popped down to sixty, and then it popped down to fifty, 0:10:29.800,0:10:32.101 and slowly it went down to a much smaller number. 0:10:32.101,0:10:36.270 In fact, we found out that the human genome is probably not as complex 0:10:36.270,0:10:39.505 and doesn't have as many genes as plants do. 0:10:40.721,0:10:49.050 So that then made us really question, "Well, if the genome has less genes in this species versus this species, and we're more complex potentially, 0:10:49.679,0:10:50.969 what's going on here?" 0:10:51.446,0:10:56.789 Now scientists estimate there are probably less than thirty thousand genes. 0:10:57.804,0:11:09.219 We believed - I believed naively - that we would be able to find the genetic components of common diseases. 0:11:09.219,0:11:11.290 And that's proven to be very difficult. 0:11:11.290,0:11:16.129 The idea of "one gene, one disease" does not explain it all. 0:11:16.129,0:11:20.803 Thirty thousand genes didn't appear enough to explain human complexity. 0:11:20.803,0:11:23.460 There had to be something they'd missed. 0:11:27.274,0:11:34.363 The first hints of what was missing lay in the curious paradox of the Prader-Willi and Angelman's syndromes - 0:11:35.286,0:11:40.795 - two quite different diseases caused by exactly the same genetic fault. 0:11:42.702,0:11:49.112 When Pembrey looked at the inheritance pattern for the conditions, he noticed something even stranger. 0:11:49.112,0:11:55.897 What really mattered was the origin of the chromosome fifteen that had the deletion. 0:11:55.897,0:12:01.174 If the deletion was on the chromosome fifteen that the child had inherited from father, 0:12:01.497,0:12:03.628 then you'd have Prader-Willi syndrome, 0:12:03.628,0:12:10.683 whereas if the deletion was inherited from the mother, you had the Angelman's syndrome. 0:12:11.145,0:12:17.323 It was a complete surprise that the same missing strip of DNA could cause one disease when it came from the mother, 0:12:17.662,0:12:21.793 and a completely different disease when it came from the father. 0:12:22.270,0:12:25.374 It was as if the genes knew where they came from. 0:12:26.482,0:12:34.699 You've got a developing fetus manifesting this condition ... how does the chromosome fifteen know where it came from? 0:12:34.699,0:12:41.284 It - there must have been a tag or an imprint placed on that chromosome 0:12:41.284,0:12:46.015 during either egg or sperm formation from the previous generation 0:12:46.015,0:12:49.308 to say, "Hi! I came from mother. I came from father. 0:12:49.308,0:12:51.672 And we are functioning differently." 0:12:51.672,0:12:56.433 So that's the key thing: that although the DNA sequence is the same, 0:12:56.433,0:13:03.693 the different sets of genes were being silenced depending on whether it came from the mother or from the father. 0:13:05.477,0:13:12.230 It showed that there was clearly more to inheritance than simply the coded sequence of DNA. 0:13:12.568,0:13:19.152 We then realized that we were dealing with what is now known as genomic imprinting. 0:13:19.768,0:13:29.785 What genomic imprinting means is, in a nutshell, that genes have a memory of where they came from. 0:13:32.293,0:13:39.223 Something other than just the DNA was capable of moving between generations. 0:13:42.901,0:13:48.174 It was a tantalizing glimpse into this unknown and unexpected world. 0:13:48.697,0:13:54.983 A hidden layer acting on, and able to directly control, how our genes function. 0:13:56.844,0:14:01.261 It meant that inheritance was not simply about which genes you inherited, 0:14:01.261,0:14:06.573 but whether those genes were silenced; switched on, or off. 0:14:06.681,0:14:09.270 And you can think of it as a light switch. 0:14:13.579,0:14:21.049 Switch on the gene, the light is shining, the gene is active, it makes the cell do a certain thing; 0:14:22.156,0:14:27.550 or the light switch is off, everything is dark, that gene is off. 0:14:27.580,0:14:33.716 The switches remain on or remain off. And that gives the cells their identity. 0:14:34.702,0:14:38.798 The activity of genes was being controlled by a switch: 0:14:39.814,0:14:46.511 the attachment of a simple chemical which dictated whether the gene was switched on or off. 0:14:48.311,0:14:52.122 Whether those genes are turned on or off is called epigenetics. 0:14:52.122,0:14:58.047 Epigenetics. You know, "upon" the genes. 0:15:00.323,0:15:05.850 Not only is the sequence important of the DNA, which we've studied for a long time, (the past few decades) 0:15:05.850,0:15:08.030 but we now understand that in addition to that 0:15:08.030,0:15:13.914 there's this overlying epigenetic phenomenon that allows the genes to get turned on or off. 0:15:14.236,0:15:20.284 Epigenetics could explain how a human could be created with less than thirty thousand genes, 0:15:20.284,0:15:24.617 and why the genome project didn't provide all the answers. 0:15:24.617,0:15:27.282 Now if we actually put epigenetics on top of it - 0:15:27.282,0:15:31.870 - where it makes it much more complicated on whether genes get activated to a certain level and so forth - 0:15:31.870,0:15:38.900 - then you have a complexity that can start to explain biology much more effectively than the simple sequence of the DNA. 0:15:38.900,0:15:45.081 So clearly we have additional levels of complexity that we now need to understand that are well beyond the DNA. 0:15:45.081,0:15:51.979 The next huge challenge for modern biology is to now decipher the epigenetic code 0:15:51.979,0:15:57.446 and to understand all the combinations of switches that exist. 0:15:58.323,0:16:05.263 An accurate chemical map of the human genome tells us surprisingly little about how it actually works. 0:16:06.063,0:16:14.282 Transcribing the code of the genes - the genome project - is not an end, but simply a beginning. 0:16:19.867,0:16:30.710 If inheritance was not just about DNA, if these gene switches were so important, just what could turn them on, or off? 0:16:40.389,0:16:45.817 Stephanie and Amon Mullins have two children: Ciaran and Charlotte. 0:16:45.817,0:16:51.721 When you are trying to conceive, and you see all your friends around you getting pregnant, having children, 0:16:51.721,0:16:55.195 as each month went on you become more and more desperate. 0:16:55.826,0:16:58.795 Doctors recommended IVF treatment. 0:16:59.349,0:17:07.543 In the UK alone, around eight thousand babies are conceived every year using assisted reproduction techniques like IVF. 0:17:10.249,0:17:14.848 After the third attempt, Stephanie became pregnant with Ciaran. 0:17:15.371,0:17:19.673 At the time they didn't really highlight any risks to us. 0:17:20.580,0:17:28.227 And then we went for a routine scan, and I did feel that the scan was taking an awful long time. 0:17:30.536,0:17:36.506 Basically what they'd found was something called an exomphalus on Ciaran's abdomen, 0:17:36.506,0:17:43.593 which basically means that part of the bowel is still on the outside of the abdomen. 0:17:45.408,0:17:50.564 Doctors suspected that Ciaran might be suffering from Beckwith-Wiedemann syndrome, 0:17:50.778,0:17:59.528 a rare condition where babies are born very large, often have oversized tongues, and have a high risk of developing childhood cancers. 0:18:01.174,0:18:05.541 They couldn't say one hundred percent that the baby did have Beckwith-Wiedemann syndrome, 0:18:05.541,0:18:08.179 but it was showing signs. 0:18:09.332,0:18:14.334 They could see his tongue protruding on the scan, 0:18:14.334,0:18:18.586 and he said that he had very big thighs, 0:18:18.586,0:18:24.374 but until Ciaran was actually born, we didn't know how severely affected he was going to be. 0:18:25.651,0:18:31.774 When Ciaran was born, it was clear he did indeed have Beckwith-Wiedemann syndrome. 0:18:34.282,0:18:36.810 Within a few hours of the birth, 0:18:37.410,0:18:45.030 Ciaran had to have surgery to have the bowel that was on the outside of the abdomen basically put back inside, repaired. 0:18:46.030,0:18:55.532 Ciaran also had surgery to reduce the size of his tongue, and every few months he has scans to check for tumors. 0:19:00.455,0:19:05.787 Cases of Beckwith-Wiedemann syndrome caught the attention of Wolf Reik. 0:19:10.126,0:19:13.586 Wolf Reik worked in developmental genetics. 0:19:13.632,0:19:18.274 He was fascinated by the emerging epigenetic ghost world. 0:19:18.274,0:19:23.258 He wanted to know what could throw the switches on or off. 0:19:24.704,0:19:34.104 To his surprise, he found that simply placing a mouse embryo in a culture dish could trigger genes to switch off. 0:19:36.027,0:19:43.817 After we had seen how relatively easy it was to change the switches in mouse embryos, 0:19:43.817,0:19:49.719 we thought that perhaps the same could be true of human embryos. 0:19:51.181,0:19:57.684 In IVF you also have the embryo for a brief period of time in a culture dish. 0:19:57.838,0:20:02.803 And so we were asking the question whether, as in the mouse embryo, 0:20:02.803,0:20:12.975 the mere fact of human embryos having been in a culture dish or being manipulated could alter their epigenetic switches. 0:20:14.559,0:20:19.951 Wolf knew that Beckwith-Wiedemann syndrome was caused by a faulty switch. 0:20:20.428,0:20:27.867 So what we were looking at was a group of babies and children that have Beckwith-Wiedemann syndrome. 0:20:27.867,0:20:32.268 What proportion of those were conceived by IVF? 0:20:33.345,0:20:40.342 Could IVF be switching genes on or off? Could IVF itself cause the syndrome? 0:20:41.634,0:20:51.564 What we found was an increased occurrence of this epigenetic syndrome in the IVF population. 0:20:52.426,0:20:59.778 Although the disease is extremely rare, the risk appeared to increase three to four times with IVF. 0:20:59.778,0:21:06.730 It seemed that the simple act of removing the embryo from its natural environment could trigger the disease. 0:21:07.637,0:21:15.158 And we do feel frustrated that Ciaran might possibly have Wiedemann syndrome because we had IVF. 0:21:15.158,0:21:18.534 But at the time it was the right decision to make. 0:21:18.534,0:21:22.946 And I think that's why we should look again at the IVF procedures, 0:21:22.946,0:21:25.019 the conditions that are being used, 0:21:25.019,0:21:33.671 and carry out better and more precise experiments to see how we can avoid throwing these epigenetic switches. 0:21:36.656,0:21:43.531 Wolf had shown a simple change in environment was enough to turn a gene on or off, but there was more. 0:21:49.624,0:21:54.101 Everyone thought that any altered switches could not be inherited. 0:21:56.209,0:22:00.369 He took some mice with altered gene switches and bred them. 0:22:01.462,0:22:13.463 Our expectation was that as the altered genome was passed to the children that any epigenetic changes would be wiped clean. 0:22:15.294,0:22:19.738 When he looked at the gene profile of the offspring he was amazed. 0:22:21.184,0:22:27.375 You have dots that we were looking at, and every dot means a gene is on. 0:22:27.837,0:22:31.974 And all of the sudden you know somebody said, "Wow - look at that." 0:22:31.974,0:22:39.096 The epigenetic switch thrown in one generation was clearly also present in the second generation. 0:22:40.373,0:22:44.420 Nobody had seen this kind of thing before. This was the first time. 0:22:44.420,0:22:49.283 And all the people looking at the gel and saying, "No, this can't be right, it's the wrong gel." 0:22:49.283,0:22:56.195 And you know, you get excited about it and you think, "Oh, maybe this is wrong," and you're not on the right track. 0:22:56.195,0:23:02.825 And we were very excited - as excited as scientists ever get. 0:23:04.902,0:23:08.834 This meant that the genes were not locked away. 0:23:08.834,0:23:13.722 A simple environmental event could affect the way genes worked. 0:23:13.722,0:23:24.068 And that could be inherited, as if a memory of an event was being passed down through generations. 0:23:24.176,0:23:27.824 It was something many scientists regarded as impossible. 0:23:27.824,0:23:33.106 If this effect could be observed in humans the implications would be profound. 0:23:33.106,0:23:44.318 It would mean that what we experience could affect not just us, but our children and our grandchildren. 0:23:50.319,0:23:57.833 While these observations were just emerging from laboratories, Pembrey was still working at Great Ormond Street. 0:23:57.833,0:24:03.690 He began to wonder why these links between generations would exist. 0:24:03.690,0:24:13.220 Now my reputation was made as a clinical geneticist, so I was much freer to speculate outside my main career. 0:24:15.098,0:24:21.985 I also like to stir things up a bit. And it amuses me to speculate because I've got nothing to lose. 0:24:21.985,0:24:25.942 And if I'm right, well then that's very amusing. 0:24:26.911,0:24:32.846 He speculated why genes would carry a memory from one generation to the next. 0:24:32.846,0:24:37.089 What evolutionary purpose could it serve? 0:24:38.165,0:24:44.229 Maybe imprinting was used as a means of some sort of trans-generational adaptation. 0:24:46.630,0:24:53.513 He thought it could be used for a mother to send messages to her baby in the next generation. 0:24:55.528,0:24:58.313 Something that always puzzled me ever since I was a medical student was 0:24:58.313,0:25:02.375 what stops the baby's head jamming up in the birth canal? 0:25:02.375,0:25:08.274 The baby was grown in one generation, but the mother's pelvis was grown in the previous generation. 0:25:08.274,0:25:13.104 So if the mother was starving when she was growing, (so she had a small pelvis) 0:25:13.427,0:25:24.812 maybe her eggs had captured that information and so they were instructing the growth genes of the future babies to not work so much, 0:25:24.812,0:25:29.259 and for the baby not to grow too much so as to jam up the birth canal. 0:25:29.259,0:25:33.202 So, there was some sort of coordination between growth in two generations. 0:25:33.202,0:25:35.872 That struck me as entirely reasonable. 0:25:36.056,0:25:40.846 He published his ideas in an obscure journal and largely forgot about it. 0:25:40.846,0:25:45.634 After all, there was no evidence for any of this. It was pure speculation. 0:25:48.788,0:25:53.326 Then four years later Marcus received an email from a doctor in Sweden.[br] 0:25:53.934,0:25:55.717 It really came as a bolt out of the blue. 0:25:55.717,0:26:08.094 I'd just got an email in May 2000 saying my paper was the only thing he could find in the literature that in any way sort of tied in with his basic observations. 0:26:09.341,0:26:12.203 The email was sent by Olov Bygren. 0:26:12.203,0:26:19.248 He was studying the population records of an obscure town in northern Sweden: Overkalix. 0:26:23.663,0:26:27.059 What made these records unique was their detail. 0:26:27.059,0:26:30.247 They recorded births and deaths over hundreds of years. 0:26:30.247,0:26:34.105 They also had accurate details of the harvests. 0:26:38.505,0:26:46.670 More significantly, Overkalix's isolated location on the Arctic Circle meant that it was particularly vulnerable to famine. 0:26:53.040,0:26:56.986 In the nineteenth century this was a very isolated area. 0:26:56.986,0:27:00.041 They could not have help from outside. 0:27:00.041,0:27:05.964 As it was so poor, they really had a hard time when there was a famine. 0:27:05.964,0:27:12.126 And they really had a good time when the harvests were good. 0:27:13.725,0:27:19.713 Bygren appeared to be seeing links between generations that confounded his expectations. 0:27:20.344,0:27:30.011 I sent Marcus Pembrey an email telling him that we had some data which could interest him. 0:27:33.335,0:27:37.271 I was terribly exited to get this completely out of the blue, 0:27:38.594,0:27:45.032 and for the first time it seemed that there was some data that we could then start to explore. 0:27:45.032,0:27:48.077 So that was the beginning of our collaboration. 0:27:48.077,0:27:51.612 Overkalix offered Pembrey a unique opportunity 0:27:51.612,0:27:59.032 to see if the events that happened in one generation could affect another, decades later. 0:28:06.724,0:28:10.858 While Pembrey and Bygren sifted through the Overkalix data, 0:28:10.858,0:28:16.936 someone else had stumbled on another group of people that caught them by surprise. 0:28:20.445,0:28:26.241 Rachel Yehuda is a psychologist. She's interested in how people respond to stress. 0:28:26.241,0:28:33.576 Well trans-generational effects were not on my radar screen at all, until we opened up a clinic for the treatment of Holocaust survivors. 0:28:38.347,0:28:41.534 While treating the Holocaust survivors for stress, 0:28:41.534,0:28:48.419 she was surprised that many of the children of the survivors were themselves suffering stress effects. 0:28:48.419,0:28:54.151 About five children of Holocaust survivors were calling us for Holocaust survivor, 0:28:54.151,0:29:04.694 and what these children said is that they were casualties of the Holocaust too - that they had been affected by the Holocaust indirectly. 0:29:04.694,0:29:11.334 She was convinced that the stress in the children was caused by continual re-telling of the stories by their parents. 0:29:15.103,0:29:17.994 Our studies had really convinced me 0:29:17.994,0:29:31.034 that it were the early experiences of the child as the child was growing up bombarded with years and years of symptoms from the parents 0:29:31.034,0:29:34.884 that accounted for the effect that we observed. 0:29:34.884,0:29:41.955 However, in Edinburgh, Jonathan Seckl was interested in stress exposure in pregnant women 0:29:41.955,0:29:47.235 and wondered if stress effects could be transmitted to their children. 0:29:47.235,0:29:56.425 He started some experiments with pregnant rats to see if exposing them to stress hormones had any effect on their offspring. 0:29:56.425,0:30:00.724 And we found the next generation, for the rest of their lifespan, 0:30:00.724,0:30:06.809 those animals had altered stress responses and showed behavior that looked like anxiety. 0:30:06.809,0:30:09.722 To see if this was affecting the genes themselves, 0:30:09.722,0:30:18.577 he decided to breed them and see if the stress effects could be found in generations never exposed to the stress hormone. 0:30:18.577,0:30:24.889 And their daughters and sons also got the propensity for abnormal stress responses. 0:30:24.889,0:30:34.154 For Seckl the only explanation was that a stressful event was throwing a switch on a gene which was then being inherited. 0:30:39.138,0:30:43.137 His work might have stopped there, until world events took a hand. 0:30:46.006,0:30:49.932 When on 9-11 the planes crashed and the towers came down, 0:30:49.932,0:30:59.698 Yehuda and Seckl were critically aware of the potential for the impact to be far-reaching - even affecting generations yet to be born. 0:30:59.698,0:31:04.280 Ailsa Gilliam was working in a building next to the towers. 0:31:04.280,0:31:13.055 As I left my building coming out through the doors, there was a lot of ash floating through the air, and some office papers. 0:31:13.055,0:31:18.603 I knew that if I looked up I may see something I didn't want to see. 0:31:18.603,0:31:28.079 Just the thought that people had died close to me? I broke down. I got very upset. 0:31:28.927,0:31:31.116 Well I wanted to get out of the environment. 0:31:31.116,0:31:39.812 Being pregnant, I did not want to open myself up to more emotional uncertainty and emotional distress. 0:31:40.966,0:31:50.167 After the events of 9-11 unfolded, Yehuda and Seckl teamed up to study women like Ailsa who were pregnant at the time. 0:31:50.167,0:31:57.092 There were a lot of different opportunities to examine what the effects of 9-11 would be 0:31:57.092,0:32:04.608 on the children who might be born to parents who developed Post-Traumatic Stress Disorder in response to 9-11, 0:32:04.608,0:32:10.325 and particularly those who had been exposed in utero.[br] 0:32:20.250,0:32:28.451 When exposed to a stressful event a person produces cortisol, a hormone that helps regulate the body's response to that stress. 0:32:28.451,0:32:39.936 If cortisol levels are too low, a person finds coping with stress very difficult and are prone to PTSD: Post-Traumatic Stress Disorder. 0:32:40.305,0:32:44.550 But could this effect be transmitted to their offspring? 0:32:44.550,0:32:51.013 They found nearly two hundred women of whom a number had actually been in the twin towers. 0:32:54.860,0:32:59.963 About half of them developed Post-Traumatic Stress Disorder. 0:32:59.963,0:33:05.577 We then looked at those women and found they had abnormal cortisol in their saliva. 0:33:05.577,0:33:10.068 The most striking finding was, so did their babies. 0:33:11.792,0:33:15.311 The argument in the Holocaust survivors had been that 0:33:15.311,0:33:19.548 their children showed abnormal stress hormones 0:33:19.548,0:33:27.670 because they themselves had been stressed by listening to the tales recounted by their parents of their awful exposures during the 1940's. 0:33:27.670,0:33:32.689 That could not be the case with the 9-11 survivors. These babies were one year old. 0:33:35.415,0:33:44.212 Not only did infants have lower cortisol levels, but they were different depending on how pregnant the mother was on 9-11. 0:33:44.212,0:33:50.987 The main effect was only seen with those mothers with PTSD who were pregnant in the last third of pregnancy. 0:33:50.987,0:33:56.759 Mothers with equal levels of PTSD who were pregnant in the first and second third of pregnancy at 9-11 ... 0:33:56.759,0:33:59.871 ... it was very little effect on the baby's cortisol. 0:33:59.871,0:34:03.012 It suggested to us that it couldn't just be about genetics, 0:34:03.012,0:34:08.030 but there was something that was being transmitted in the late stages of pregnancy 0:34:08.030,0:34:16.617 where the mother's symptoms were having some effect on the development of the offspring's cortisol system. 0:34:18.664,0:34:26.473 It appeared that epigenetics might be responsible; that an event had altered the stress response in the children. 0:34:26.473,0:34:29.939 What these findings did was suggest to us 0:34:29.939,0:34:35.237 that we need to be looking where we hadn't even considered looking before. 0:34:35.237,0:34:38.523 To know for certain that this was an epigenetic effect 0:34:38.523,0:34:44.879 they'll need to be sure that their observations weren't simply due to high levels of stress hormones in the womb. 0:34:45.309,0:34:49.406 Now, (and here is the bit where we have to speculate) 0:34:49.406,0:34:56.353 the animal work would suggest that this might then persist into the next generation. 0:34:56.384,0:35:01.386 If they find the same stress effects in the children's children of 9-11 0:35:01.386,0:35:09.017 then it will be clear that a genetic memory of a stressful event can travel through the generations. 0:35:09.017,0:35:10.882 That's the key thing next to find out. 0:35:10.882,0:35:18.973 But the 9-11 population will be very, very important for us to be able to follow what is a single discrete event. 0:35:18.973,0:35:26.388 The work of Yehuda and Seckl offers tantalizing evidence of proof of inherited epigenetic effects in humans, 0:35:26.388,0:35:31.677 but they need data that extends beyond just one generation. 0:35:35.123,0:35:39.485 The only way forward was to look back to the past. 0:35:39.485,0:35:48.746 In Sweden, Pembrey and Bygren had data that provided the chance to study the effects of famine through many generations. 0:35:53.530,0:36:02.783 Olov Bygren was looking to see if poor nutrition had an effect on health, when he stumbled on something curious. 0:36:09.582,0:36:18.433 It appeared that a famine could affect people almost a hundred years later, even if they never suffered a famine themselves. 0:36:20.202,0:36:25.410 He wanted to know how this might be possible, so he asked Marcus Pembrey. 0:36:27.287,0:36:36.266 Olov first reported that the food supply of the ancestors was affecting the longevity or mortality rate of the grandchildren. 0:36:37.511,0:36:41.367 So I was very excited. I responded immediately. 0:36:41.843,0:36:49.562 Pembrey had a hunch that the incidents of one disease, diabetes, might be an indicator that epigenetics was involved. 0:36:50.408,0:36:57.706 Specifically I wanted to know the results of the diabetes because this was the one that I thought might involve the imprinting. 0:36:59.029,0:37:02.866 So Olov trawled the records for any deaths due to diabetes 0:37:02.866,0:37:09.489 and then looked back to see if there was anything unusual about the diet of their grandparents. 0:37:11.134,0:37:19.402 A few months later, he emailed me to say that indeed they had shown a strong association 0:37:19.402,0:37:30.276 between the food supply of the father's father and the chance of diabetes being mentioned on the death certificate of the grandchild. 0:37:30.276,0:37:33.758 So of course I was really rather excited by that 0:37:33.758,0:37:38.714 because it really did look as if there was some trans-generational effect going on there. 0:37:39.729,0:37:47.177 It looked as if there were clear links through the generations between grandparents and grandchildren. 0:37:47.193,0:37:54.461 They found that the life expectancy of grandchildren was being directly affected by the diet of the grandparent. 0:37:55.615,0:38:02.858 It appeared that Overkalix held the key to finding the first evidence of epigenetic inheritance in humans. 0:38:04.643,0:38:12.441 It really did look as if there was some new mechanism transmitting environmental exposure information from one generation to the next. 0:38:15.149,0:38:23.767 Because these ideas were so heretical, Pembrey knew these results could be dismissed as nothing more than a curiosity. 0:38:25.074,0:38:28.700 They needed to get an understanding of how all this was happening. 0:38:28.977,0:38:34.861 How could the grandparent capture the information that was affecting the grandchildren? 0:38:37.108,0:38:44.797 We wanted to tease out when you could trigger in the ancestor a trans-generational response. 0:38:45.566,0:38:49.665 So he and Bygren went back to the data and looked again. 0:38:50.388,0:38:54.391 The more they looked, the more patterns started to appear. 0:38:55.037,0:38:58.990 We were able to look at the food supply. 0:38:59.790,0:39:07.983 Every year in the grandfather and the grandmother from the moment they were conceived right through until the age of twenty. 0:39:07.983,0:39:13.073 We found that there were only certain periods in the ancestor's development 0:39:13.073,0:39:23.085 when they can trigger this trans-generational response - their, what one might call, "sensitive periods" of development. 0:39:23.085,0:39:32.285 They discovered that when a famine was able to trigger an effect was different for the grandmother than the grandfather. 0:39:32.777,0:39:38.719 The grandmother appear susceptible while she herself was still in the womb, 0:39:38.857,0:39:43.488 while the grandfather was affected just before puberty. 0:39:44.826,0:39:48.140 And the timing of these sensitive periods was telling us 0:39:48.140,0:39:52.972 that it was tied in with the formation of the eggs and the sperm. 0:39:52.972,0:39:58.086 This was critical, because now they knew how it was happening. 0:39:58.655,0:40:07.267 Environmental information was being imprinted on the egg and sperm at the time of their formation. 0:40:07.267,0:40:14.955 At last a clear picture of an inherited environmental effect was beginning to emerge. 0:40:15.937,0:40:20.839 All they needed to do now was to compile their findings. 0:40:20.839,0:40:26.688 Bygren drew up a rough diagram and sent it to Pembrey. 0:40:28.580,0:40:31.074 Hand-drawn, this is what Olov sent me. 0:40:31.074,0:40:33.842 You know, he was too excited to wait for the thing to be drawn out, probably. 0:40:33.842,0:40:36.300 You know, he sent me the data. 0:40:36.300,0:40:39.903 And in fact I was recovering from having something done to my heart, 0:40:39.903,0:40:47.602 so he sent it saying, "I hope this helps you get better quickly," because he was so excited. 0:40:47.602,0:40:55.036 When Pembrey plotted out the diagram, he was immediately struck by its significance. 0:40:55.036,0:41:03.098 Once I had plotted out the full extent of those results, it was so beautiful and such a clear pattern. 0:41:03.098,0:41:09.186 I knew then quite definitely that we were dealing with a trans-generational response. 0:41:09.186,0:41:10.915 It was so coherent. 0:41:10.915,0:41:15.696 And that's important in science, that the effect was coherent in some way. 0:41:15.696,0:41:19.965 It was tying in when eggs and sperm were being formed.[br] 0:41:19.965,0:41:30.246 The diagram showed a significant link between generations: between the diet in one and the life expectancy of another. 0:41:30.246,0:41:45.174 When you think that you have found something important for the understanding of the science itself you can then imagine that this is something really special. 0:41:46.128,0:41:49.918 It's up there with - I'm a sort of fair weather supporter of Liverpool - 0:41:49.918,0:41:53.977 - it's up there with Liverpool winning the Champions League. 0:41:53.977,0:41:57.687 You can only have it once in your lifetime. 0:41:57.687,0:42:00.908 This is going to become a famous diagram, I'm convinced about that. 0:42:00.908,0:42:03.252 I get so excited every time I see it. 0:42:03.252,0:42:11.580 It's just amazing. Every time I look at it I find it really exciting. It's fantastic. 0:42:11.580,0:42:22.850 Pembrey and Bygren have the first conclusive proof of an environmental effect being inherited by humans. 0:42:26.127,0:42:33.018 The impact of a famine being captured by the genes in the eggs and sperm, 0:42:33.018,0:42:41.530 and a memory of this event was being carried forward to effect the grandchildren generations later. 0:42:41.807,0:42:46.081 We're changing the view of what inheritance is. 0:42:46.081,0:42:57.496 You can't in life - in ordinary development and living - separate out the gene from the environmental effect, they're so intertwined. 0:42:57.496,0:43:03.233 Pembrey and Bygren's work showed clearly that what our grandparents ate could affect our health. 0:43:03.233,0:43:09.581 Increasingly, it appeared as if all sorts of environmental events were capable of affecting the genes. 0:43:10.165,0:43:17.564 And in Washington State, Mike Skinner stumbled on some results with profound implications. 0:43:17.564,0:43:23.149 He triggered an effect with commonly used pesticides and fungicides. 0:43:23.317,0:43:30.840 He exposed a pregnant rat to a high dose of one of these pesticides and then looked for effects in her offspring. 0:43:30.840,0:43:35.801 And so I treated the animals (the pregnant mother) with these compounds, 0:43:35.801,0:43:42.623 and then we started seeing - between six months to a year - a whole host of other diseases that we didn't expect. 0:43:42.623,0:43:52.777 And this ranged between tumors such as breast and skin tumors, prostate disease, kidney disease, and immune dysfunction. 0:43:54.178,0:44:00.827 He bred these rats to see if the effects persisted into subsequent generations. 0:44:00.827,0:44:07.252 The next step was for us to go to the next generation, and then go to the third generation out, and the same disease state occurs. 0:44:07.252,0:44:12.815 So after we did several repeats and got the third generation showing it and then a fourth generation 0:44:12.815,0:44:17.136 we sat back and realized that the phenomenon was real. 0:44:17.136,0:44:24.289 We started seeing these major diseases occur in approximately eighty-five percent of all the animals of every single generation. 0:44:24.289,0:44:28.199 His discoveries were a revelation. 0:44:28.199,0:44:35.048 We knew that if an individual was exposed to an environmental toxin that they can get a disease state potentially. 0:44:35.048,0:44:42.182 The new phenomenon is that an environmental toxin no longer affects just the individual exposed, 0:44:42.182,0:44:46.372 but two or three generations down the line. 0:44:46.372,0:44:48.536 I knew that epigenetics existed, 0:44:48.536,0:44:53.814 I knew that it was a controlling factor for DNA activity where the genes are silenced or not, 0:44:54.584,0:45:01.442 but to say that epigenetics would have a major role in disease development ... I had no concept of that. 0:45:01.442,0:45:04.171 The fact that this could have such a huge impact 0:45:04.171,0:45:11.403 and could explain a whole host of things we couldn't explain before took a while to actually sink in. 0:45:12.541,0:45:22.856 The exposure of a single animal to a toxin was causing a whole range of diseases in almost every individual of the following generations. 0:45:22.856,0:45:29.167 And because epigenetic effects have been observed in humans this may have implications for us, too. 0:45:29.167,0:45:35.054 What this means then is what your grandmother was exposed to when she was pregnant 0:45:35.054,0:45:36.699 could cause a disease in you 0:45:36.699,0:45:38.155 even though you had no exposure 0:45:38.155,0:45:42.914 - and you're going to pass it on to your great-grandchildren. 0:45:46.114,0:45:54.689 The work of these scientists is at last throwing a spotlight onto the mysterious hidden world of epigenetics. 0:45:54.689,0:46:02.459 They appear to show that the lives of our ancestors have a capacity to affect us directly. 0:46:03.413,0:46:11.326 These results are provocative. Some find them difficult to accept. 0:46:11.326,0:46:20.968 But it's quite clear now that a number of laboratories are finding similar findings in the various systems that they are interested in. 0:46:20.968,0:46:24.092 So the phenomena are there. 0:46:25.461,0:46:29.890 Epigenetics has the capacity to reach into every aspect of our lives, 0:46:29.890,0:46:35.929 and links our past, present and future in previously unimagined ways. 0:46:35.929,0:46:39.683 I think this will be the next revolution in molecular biology. 0:46:39.683,0:46:44.878 This really could be a paradigm shift we really did not expect. It could explain a lot of things. 0:46:44.878,0:46:53.590 There are many diseases - very common diseases such as Alzheimer's disease of the brain, diabetes - 0:46:53.590,0:46:58.291 - which are very difficult to explain currently genetically. 0:46:58.291,0:47:06.092 Maybe a lot of these kind of very common diseases are actually caused by epigenetic switches. 0:47:06.338,0:47:10.929 We are just at the beginning. There is much that is unknown. 0:47:10.929,0:47:17.565 But what is clear is that it will change the way we think about ourselves forever. 0:47:17.703,0:47:22.321 I've thought of nothing else, really, for the past five years. 0:47:22.321,0:47:27.228 It is said the first time one had a photograph of the earth - 0:47:27.228,0:47:34.805 - you know, this sort of delicate thing sailing through the universe - 0:47:34.805,0:47:42.533 - it had a huge effect on the sort of "save the planet" type of feeling. 0:47:42.533,0:47:50.938 I'm sure that's part of why the future generation thinks in a planetary way, because they've actually seen that picture, you know. 0:47:50.938,0:47:53.797 And this might be the same. 0:47:53.797,0:48:08.666 It may get to a point where they realize that you live your life as a sort of guardian of your genome. 0:48:08.666,0:48:12.567 You've got to be careful of it because it's just not you. 0:48:12.567,0:48:15.192 You can't be selfish because you can't say, 0:48:15.192,0:48:22.385 "Well I'll smoke, or I'll do whatever it is, because I'm prepared to die early." 0:48:22.385,0:48:27.743 You're also looking after it for your children and grandchildren.