Dr. Marcus Pembrey provides a nice background on his experiences with imprinting and how it might provide a means for transgenerational adaptation. This short take was shot during a break at Keystone Symposia’s meeting on Environmental Epigenomics and Disease Susceptibility held in March 2011 in Asheville, North Carolina.
I’m a chemical geneticist, and in the ‘80s we were puzzled by families we were seeing in the clinic that didn’t follow Mendelian inheritance and to cut a long story short, I was involved in demonstrating the cause and imprinted nature of Angelman Syndrome on Chromosome 15 in humans, the late ‘80s, early ‘90s. So I got into imprinting pretty early, and that was useful from the point of view of advising the families I saw and so on, but at the same time, I was working with colleagues in Bristol ‘cause it’s a better location for population studies, to set up this huge prospective study of the general population.
That’s the Avon Longitudinal Study of Parents and Children. And that started in the children who were born ’91, ’92, so they’re now knocking on 20, and it’s the most comprehensively followed childbirth cohort or they were ascertained actually before birth. So I switched slowly to the issue that everybody was contemplating: what were the contributing determinants to common diseases? The Mendelian disorders had always been sorted out, by the Human Genome Project was progressing and so on, and I had to step back just a bit.
“You’ve got to look at where life meets the genome ‘cause that’s where all the action is.”
So that was the background. That was what I was doing, and Judy Hall, who was interested in imprinting, she contacted me in ’93 to say would I end the imprinting meeting in Florence ‘cause we had a group of imprinters who would move around in ’94, speculating a little bit on why humans still had imprinted genes type of thing. And I got very interested in the idea and indeed floated the idea that perhaps variation in the degree of imprinting of imprinted genes in response to sea changes in environment might allow some form of transgenerational adaptation.
So that was just theoretical. It was published in an extremely obscure journal, and I had put it on the back burner really because I realized you couldn’t study things down the female line; they were too complicated. So I was trying to think of instances of transgenerational responses down the male line, and there was only one thing called a “para-mutation” that seemed to be occurring at the insulin (the NTR) gene in humans, but then completely out of the blue, Dr. Lars Olaf Byrgen (he was a retired ____ doctor from Northern Sweden) contacted me just saying that my speculative papers, the only paper in the literature that he could find that in any way explained the fact that he’d observed that the food supply of the father’s father when he was young was influencing the longevity of the grandchildren.
And there began a beautiful collaboration. And so I was aware, of course, that if there was transgenerational imprinting effects triggered by environmental changes (adaptations), this sort of thing we would need to find as supporting of it. But having started to find it, that didn’t mean it was epigenetic, and so we’re in that state. We’ve got better and better evidence of an exposure in one generation in humans leading to outcomes in the subsequent generations that have not been exposed.
So the Swedish data we collaborated on the Swedish data for a while, identified diabetes as one of the things influenced as an outcome in the grandchildren from grandparental feeding. And then, when that turned out to be a hypothesis that turned out to be great, at least in terms of the associations (we don’t know about mechanisms), Jean Gold and I set up house back on it and decided to give it a go. She said, “Well, the only thing we can really study on the current data was what the father, when he started smoking.” That was the exposure on the father.
And then we saw, when we looked about, we were looking at birth characteristics in the early graph, and we found that indeed if the father started smoking before 11, his future sons would be born earlier and would be heavier by the age of 9. So we then got onto the streets and said why not do what we suggested originally, but they were worried about splitting their sample in half and all that stuff. Look at the sex of the grandchildren, and then we got these very dramatic patterns.
Meanwhile, Barbara Boucher, who collaborates a bit with ALSPAC, she contacted me after the television program in 2005, the Horizon program called, “The Ghost in Your Genes,” and she said, “Oh, we’ve got some stuff coming out. It’s bound to be on the Y Chromosome. This is beetle nut chewing study she’d done in Thailand. So this all took off really. It’s very nice in my retirement really. I was planning to just sort of dot a few I’s, cross a few T’s and get on with this public education side. So that’s what happened.
So the situation we’re in now is a bit paradoxical. We’ve got all this very interesting data, which I think is pretty solid as a phenomenon. It’s not just social patterning, but we have no evidence what cause is, so we can’t say it’s epigenetic at this point. We don’t know what the mediating mechanism is, but I guess its epigenetic transgeneration inheritance is the top candidate. And when the technology’s got to a point where I’m prepared to use these precious samples, we’ll see where it is.
I mean I knew from Mendelian genetics where you knew if you could sort out what gene was mutant and so on, you could really help families, but with common disease and development, we really do have to understand these transgenerational effects and gene/environment interactions where epigenetics as I say is where life meets the genome, and clearly it’s going to be playing an important part.
But the transgenerational thing could pay. I mean I’m sticking my neck out now. It could play a much bigger part than people ever imagined. You’ve got this missing inheritability; it might contribute to that, but the real thing is to understand how the human race responds to sea changes in the environment, social and physical, and we’re gonna see more and more of this with global warming threats and this sort of thing.
We need to understand how humans respond in order to understand how to plan for the future because and it isn’t they respond in one generation and you just plan for one generation. You just wait. Someone have to be and think in the bigger term. The one take-home message I guess comes from our discovery as far as we can this critical period in mid-childhood which is a time that people – the children are so compliant between six and ten. They do what we do. They’re not in the adolescent strop. They’ve got over their tantrums; they absorb all this information. People really were surprised when we found that was a hypersensitive period; that taking all this information, transmitting it I suspect to the future generations.
So the bottom line now right now is we have to continue to treat childhood seriously. We can’t just say they can be allowed to do this, and they be allowed to do that, and doesn’t matter about the future, why they can always sort of catch up. Everybody’s focusing now on the fetal and pregnancy, but this period is important, too.
Well, I think really I mean that’s the wonderful thing about scientific community. When they latch on, especially when you’ve stuck your neck out and most people thought the printing was a curiosity or whatever, and I must say I never did and I encourage all my juniors in the department to take it seriously because, of course, we had individual families that we could help there and then, but in the bigger picture, I thought it was gonna be useful.
So we had these imprinting meetings; they would move around Florence, Ireland in Dublin and so on. And you’d gradually gather this group of the “old hands,” as it were, and then there was this big explosion of interest sort of after the genome project really, and I think people are quite right in saying that it’s had an impetus from rather poor returns from simple GWAS I mean theoretically GWAS without looking at the environment interaction and things like that was never going to deliver a big thing, the hope there’d be a few low-hanging fruit, which there weren’t really.
So what’s been enjoyable is to come back and see a few old hands who’d been around for 25, 30 years on this business, and then see all these young post-docs get really excited about this and that, and there’s a real gravy train — that’s not right. Think caravan, I don’t know what the phase would be, but we’ve got a little network funded from Stockholm on a Transgenerational Response Network. We met 10 days ago, and there were people there who they went on to Newcastle, where there was an epigenetics meeting, gathering more. We’re getting more exciting and published results, and then about half of them have come on here, and it’s like a snowball. I mean in this one month, I have heard of 5, 8 new studies, 2 in humans, which are really exciting me.
That’s the good thing about science really, and there’s a terrific collegiate atmosphere here, and there’s plenty to argue about, and it’s not just handwaving now; there’s some data, you know. And I think amongst us a slightly sneaky sort of well, I told you so. You can spend all your money on your GWAS, you won’t get the answer. You’ve got to look at where life meets the genome ‘cause that’s where all the action is.