Epigenetic echoes of your mother's diet | Andrew Prentice | TEDxLSHTM

[Music] [Applause] epigenetic Echoes what on Earth is this crazy Professor going to try and tell me in the next few minutes I want to introduce you to an emerging science that promises to uncover for us the origins of life and in doing so lead potentially quite rapidly to some transformation in healthcare it requires a marriage between mathematicians and biologists between computer scientists and Physicians and it's of special interest to cancer biologists not only is it fascinating scientists but it's also grabbing the attention of the general public and I hope that many of you may have seen this last night the first in the series of countdown to life the extraordinary making of you which describes some of our work in The Gambia as we try to understand how a mother's diet in the days around conception can affect the health of that baby you see there not only is it emerges a few hours earlier from the womb but how it will affect that baby's health for the rest of its life let's start at the very beginning this lovely electron micrograph captures the moment at which a human sperm meets a human egg now this has been a tremendous Journey that sperm has had to compete against millions of others and swim what for it would be an enormous Journey up the fallopian tube and find the egg that's the easy bit then it starts to get complicated the 50% of the father's DNA that's contained in that sperm has to intermingle with the 50% of the mother's DNA that's in the egg in order to make the new u a few hours later that single cell will divide into two and a few hours later those two cells will divide again into two more to make four then 8 16 32 64 and so on and a couple of days later it'll look like this a small mass of cells that is just embedding itself on the uterus wall now each of these cells contains an identical genetic code 8,000 million base pairs the length of 800 Bibles of information which is Faithfully transcribed with almost no errors every time the cell has to divide so each cell containing the same bit of information how can they turn into different cells that create a human being and that's where epigenetics comes in the Epi in epigenetics means above upon these are messages that are written on top of the genetic code on top of our basic DNA and give instructions as to how the cells should read and express the DNA it's an incredibly complicated story as you can easily see from this picture which is one of thousands that are now appearing in journals How can any single human mind make sense of all this information it's quite impossible and so we need a new breed of biologists we call them bioinformaticians who are very skilled mathematicians who can look at this data and triage it and dig down to find the occasional Diamond that will tell us what has gone wrong in a disease and how we might be able to alter that now there are many many mechanisms by which epigenetic messages can be encoded here are just a few of them here you'll see those what look like balls of wool nucleosomes when DNA is wrapped tightly around that the Machinery that translates the DNA that translates the code cannot get at it so any Gene wrapped tightly will be silenced but there is processes which can unwrap it they're histones and they can be modified give a signal unwrap this bit let the cell read it or wrap it up again and that's happening in all of you second by second as you sit here digesting your breakfast there are slower processes micrornas thousands of these are known well at least a thousand are known uh which can be transferred from cell to cell throughout life and carry a message forward in regard of early exposures in a person the one I'm going to talk about today is methylation now there are at least 30 million points along our DNA in which they can be labeled by adding on a methy group and when that methal group is laid on again the Machinery that transcribes the DNA cannot get at it it can't read the gene so it silences it we can use music as really a very effective analogy as to what's going on here so here's a piece of bark a very famous piece piece of bark and you can see that the notes there are the DNA code that piece of bark is always the same piece of bark whether it's played on a loot or a harpsicord and we can recognize that but it can be interpreted in different ways let's just now listen to two clips which make that [Music] point [Music] so that's Mark Mark Matt herskovitz giving us a classical interpretation as most people would play it now let's hear the same piece of music in a little bit further on interpreted in a jazz [Music] manner so you see the same piece of DNA can be expressed very differently in order to create those different cells now as composing Advanced and indeed we can use this as an analogy of higher organisms as things became more complicated composers started to write down the instructions as to how they like the DNA of their music to be interpreted we have guidance as to how fast and in what way it should be played the composer says play this little bit quietly pianissimo in genetic terms that's a repressor a gene being silenced or alternatively fortisimo let's hear this loud Express this part of the gene many times over uh let's hear it within the cell and we have trans iions uh between those two different extremes so that's an analogy of what's going on in terms of the human cell now things are complicated and I'm only able to show you the very surface of the complexities so after conception the epigenetic marks that are born on the father's sperm and the mother's egg are wiped clean this process of wiping occurs very rapidly on the father's sperm it's as if the egg doesn't want it there she's scrubbing the DNA clean and getting rid of almost all the epigenetic information that has come from the Father the mother's DNA is also cleaned but not aggressively so the cleaning here happens just because it's not uh recapitulated every time the cell divides so gradually it disappears and then a few days later it's all laid back down again and in different ways in different lineages of cells that will become a heart cell or an eye cell or a brain cell but something else interesting happens there's a class of Gene called imprinted genes we don't fully understand why genes are imprinted but an imprinted Gene is where only one copy of the gene is ever read either the mother's copy or the father's copy and in order for that to be the case these need to be protected from this process of the cleaning of the DNA and the reestablishment in the very early embryo as I say we don't fully understand why that occurs but we know that it's incredibly important in terms of placental and Fetal development now here are the Posta mice the Posta children of epigenetics these are two agouti mice picture taken by my great collaborator Rob Waterland from Houston and he was famous for demonstrating that a mother's diet at the time of conception can change whether a mouse looks small and brown or large and golden these mice are identical sisters they're born in the same litter but look how different they are one of them small brown lean and healthy the other beautifully golden but massively obese and hence develops diabetes and dies much younger the same genotype but a different expression and that expression is determined by what the mother eats at the time of conception so that was great we understand that occurs in mice but does it occur in humans and we set to test that in an intriguing experiment of nature that we were very fortunate to have in our setting in rural Gambia so if we went a couple of months ago to Gambia it would look like this incidentally our lab is in those trees just north of the bear patch there which is the ubiquitous football pitch in every African village we've been working here for many years and this issue of the seasonality has intrigued us because if you went there today it would look like that and this change in the rainfall patterns creates a completely different nutritional scenario at the different times of Year mother eat very different foods at this time of year they're able to eat far more green leafy vegetables and a much more varied diet now some years ago 20 almost 20 years ago now we had observed that something very profound happens in relation to the exact month in which a baby is born which is in turn related to this seasonality here's a graph of the survival of 3,200 people that we've been you'll see that in young childhood there's no difference between those two lines really but then something profound happens at puberty and they start to stretch apart now we if we look at this section here we've just reanalyzed these recently and we kind of expected the phenomena may have disappeared but far from disappearing it's got even stronger and if you are born in the Hungry season you're over seven times more likely to die as a young adult than if you're born in the harvest season so that's a very profound effect and how could that be How Could An Early exposure lay dormant within the organism for 20 or so years and then suddenly be exposed in such a virulent way well of course we're intrigued to ask the question as to whether this is down to epigenetics now those methy groups that I told you about need a lot of nutrients in order to be produced and here are some of the pathways this incidentally is just a glimpse of the central Pathways we need some intermedium metabolites as adenosine methionine as adenosine homocystine the details don't matter but the ratio of those are important in terms of driving how many methal groups are available and those in turn are affected by all of these nutrients the B vitamins folic acid riboflavin B6 B12 CH Chine betane and methionine are particularly important so we asked the question whether mother's diets altered in these in the different seasons and as you can see here the answer was indeed yes you'll see the different yellow and blue patterns in those heat Maps according to uh the metabolites measured in mother's blood in the Hungry season and the harvest season and on the other side you see the if you look at the green line You'll see that this ratio the down toar ratio which we believe is particularly important is very different at two different times of year so the question was does this affect the epigenome of the baby now I just need to introduce you to another friend of mine metastable Epi alals don't worry about what they are it took me years to get my head around it but the simple message is that if we study these particular special genes we can tell that the action the biological action has occurred in the very first few hours or days after conception so it's just a device we use to be able to nail the time at which things have happened so we looked at seven of these and we asked the question are they different in babies who are conceived at different seasons and the answer is yes they were different now that might not look very big differences but these are very tightly biologically controlled uh processes and in fact differences this big are very meaningful but the next question was well what are these gen doing what's that going to matter to the baby and for a while the answer was we have no idea we chose these genes simply because they were metastable Epi alals as a device to look at early gestation we had no idea what they were doing but then we made a subsequent breakthrough it's in terms of this Gene here vtrna 2-1 again the details don't matter to you except to say that this is a crucial Gene at the center of imuno metabolism it affects our susceptibility to viral infections and later in life it becomes a tumor suppressor Gene so highly likely to have an important effect on human health and we see something fascinating going on here I told you about imprinted genes now this is an imprinted Gene it's maternally imprinted the mother's copy should be 100% methylated And The Father's copy should be clean and so if we measure the average DNA methylation we should get 50% and indeed for the vast majority of children we get give or take 50% but look what's happened in those primarily that are conceived in the dry season they've lost this methylation the biology has gone wrong and there's another group here with an intermediary uh effect and this is highly significantly determined by the season of conception and we believe by the mother's diet so this Gene is just acting as a canary in the coal mine if you like it's a good example of something that really matters and is affected by the mother's diet we already have evidence that there are many more behaving like this so where can this take us can some of this basic Discovery Science lead to something that will actually be useful to the world can we design Next Generation interventions that are going to make a difference to Mother's babies and we believe the answer is yes if we can work out more of the details as to how a mother's diet at the time of conception affects these epigenetic processes and how those epigenetic processes affect disease patterns cancers diabetes obesity then in principle we should be able to advise mothers what they should eat before conception or even design supplements for them that would help to clean up all these errors that occur when the diet is suboptimal and so that's our long-term aim and we hope with further Endeavor that we'll get there before too long thank [Music] you

Channel: TEDx Talks

Views: 47,992

Keywords: TEDxTalks, English, United Kingdom, Health, Cells, Children, Coding, Design, Disease, Environment, Genetics, Human origins, Nutrition, Public health, Women

Id: 32t098-z-mY

Length: 17min 17sec (1037 seconds)

Published: Mon Nov 09 2015