What is Epigenetics? - with Nessa Carey

It's wonderful to be here at the Royal Institution, it's very exciting, it's fantastic and it's great to have the opportunity to talk to you about

epigenetics

, which is actually a very new field of biology in which many cutting-edge things are being developed, but that I love it because part of it comes from simple, really direct questions and I think sometimes that's a real beauty of modern biology, so that's

what

I'm going to talk about. I'm just checking the watch because you can't see it from here even once. the lights are out, here we go, you can't talk about

epigenetics

without talking about genetics right now, this is the representation of the famous DNA double helix and back in 2001, when the human genome sequence was first published, There was a huge circle around Some pretty entertaining things were said, so there was a big press conference and that quote on the top left, today we're learning the language in which God created life, that was President Bill Clinton.

Now I can't imagine

what

it looked like during a whole room full of scientists presenting their life's work for a politician to get up and start talking about God, it must have been a great moment, the one below isn't actually there. much less overrated, is by Michael Dexter, who was president of the welcome fund that invested an enormous amount of money in this project and described the sequencing of the human genome as an outstanding achievement in terms of human history. Now I think we could discuss that a little bit, um, the written alphabet, the wheel, shooting the number zero, all of those.

We could argue that it may have had a little more impact, but the human genome sequence is very important. The human genome, our DNA, is made up of only four letters, but those four letters are used over and over again to create this extraordinary volume that is us and in fact, you inherit 3 billion of those letters from your mother and 3 billion of your father, so three billion letters from each father and sometimes all it takes is one of them is wrong and you can suffer a devastating disease, so genome sequencing is really important. but it's not all there is and we've known that for a long time because we know about these things called epigenetic phenomena and I'll explain that term in a moment, but let me give you some examples first.

You can inbreed in the laboratory. mice and I have to warn you if any of you really like mice, they appear a lot in this presentation, not always in a good way, anyway, you can shade laboratory mice and keep them in absolutely identical conditions so that the mice are as inbreds that are genetically the same as each other and the lab conditions are exactly the same and yet the mice are not identical, they will vary for example in things like body weight and this has been known for a long time since at least in the 1920s it was given a particular name as a phenomenon, it was called intangible variation, yes, exactly, it's a great example of where in biology we see something we don't understand, we give it a fancy name and we just park it, um. a worm and a fly a worm and a fly look completely different from each other and yet they have the same genetic code that they should have, there is no genome fairy that shows up and gives a worm a new pair of jeans when pupates in an adult fly. crocodiles in mammals it is very easy to understand the gender if you were to take DNA from this gentleman here and this lady, and I advise you to always get that part right.

I did it in a very dark conference room, it was horrible once, it never really recovered. but if I took DNA from these two people and sequenced it, I could tell which one came from the man and which one came from the woman, because in mammals gender is determined by whether or not we have a chromosome and if I took DNA from a male and a female crocodile Of crocodile I would sequence it and I couldn't say which comes from the male and which from the female because in crocodiles those fabulous descendants of the dinosaurs in the crocodiles the gender is not determined by genetics, it is determined by the temperature at which the eggs yeah what could be a very strange consequence of global warming we will see a skew in crocodile populations just to add all the other concerns so in all of these situations we have scenarios where we have two things that are genetically indistinguishable and yet, those two things are different from each other and are known as epigenetic phenomena.

Basically, two things are genetically identical and yet, in terms of their phenotype and their appearance, they are different from each other and the word Epi is simply from the Greek and means in addition to so it also means that there is something else operating besides the code genetic. Now these are all beautiful examples of epigenetics, but there is one that is even better. In fact, there are 300 examples of it in this room. because each of us is a masterpiece of epigenetics, each of us starts from one cell and ends up formed from about 70 trillion cells just to give you an idea of ​​how big of a number that is if you were to take this lady and to dissolve it into its individual cells, which I won't do and give them to this lady to count and I say you have to count one cell per second and when you're done you can go get a coffee, she'll get her caffeine fix. a million and a half years ago.

I love that number partly because it really shows how complicated we are and partly because about 15% of the audience is now sitting there trying to work out in their heads whether I have the math right, so I can say whatever I want for the next few 10 minutes, that's great, there are a huge number of cells in the human body and with the exception of a small percentage of cells in our immune system, all of those cells are exactly the same as each other on a genetic level. they all have exactly the same DNA code and yet kidney cells are different from liver cells, skin cells are different from uh, I can't, I think of other brain cells, here we go, and the types of cells are not only different, but they stay different, that's why you don't get teeth in your eyes I wanted to call my first book toothless in your eyes and my editors said it lacked a certain seriousness, so we are epigenetic phenomena and this should basically lead us to ask the most important question in biology: The most important question in biology is always: how can it be that a single DNA genome, a set of instructions, can lead to so many different results?

Why do I have at least 200 different types of cells, all of them with the same DNA code? This is because DNA is a script, it is not a template, and you can modify a script and by modifying it, like sticking sticky notes on a script or writing with a pencil, etc., you can get different results and I have given examples of that there are two films separated by about 60 years they use the same script which is the very good film Romeo and Juliet ok who are the actors in the black and white one Leslie Howard and masir I love it u3a it is the first time that someone has done it well wonderful and who are the actors below, you know what?

No matter the age when ever AR this you get, I say who are the act and you get Leonardo DiCaprio, you're always in pretty loud voices, right, yeah, Shakespeare. completely different script Productions okay and that's what our DNA does, that's what we can do with our DNA, so what's new in the last 20 years or such wonderful things have started happening in epigenetics and the best way How I can convey this is using a still image. about this movie what is this movie the time machine very, very good um time machine does anyone know that time machine up there in which comedy it appeared relatively recently very good Big Bang Theory excellent good good well so basically there's a wonderful scene in The Time Machine Rod Taylor, who recently died playing the time traveler and at this point in the movie he's only made a model of his time machine and he's reunited with his scientist friends.

The movie is set in the Edwardian era and was filmed in the '60s, so of course. all the scientists that come to see him are all men, so all these BLS sit around the table and tell him, like the time traveler's Bea, how his time machine will work and he says, well, the time traveler will You'll sit in that little seat and when you want to go forward, you'll push that lever forward, and when you want to go back in time, you'll pull that lever back, and everyone's like, "Oh, okay, like I explained it, and of course, it has done".

He didn't explain it, all he has done is describe it and so far all I have done for you is describe epigenetics. The reason why it is now such an exciting field of biology is because we not only have the description, we have the explanations and the explanations are all related to this now this is what DNA looks like in a cell, although it is not the famous multicolored double helix of DNA, but it is not in our cells as a long, fibrous molecule, it is wrapped around eight protein molecules, each of those protein molecules is shaped like a fist and there is a group of eight of them and what What you can see is that there are tails sticking out of the protein molecules, so you have eight proteins together.

DNA wrapped around them. Tails that stick out. This image represents the culmination of a huge amount of work by many researchers and it cost millions to generate the data that allowed this image to be created and it is fabulous, but from my point of view, trying to communicate something about science has some limitations, one is that if you're not used to this type of images it's a little overwhelming every time I upload this image I can literally see the audience going crazy so it's a little overwhelming. The other problem from my point of view is that it is very difficult to adjust it. show you the things I want to show you and I decided I needed an improved version of this so I created one now mine was an improvement because it didn't cost millions.

I was able to adapt it to show you the things I needed to explain. and then once I adapted it and photographed it, I ate it, because mine is made of strawberry laces, marshmallows, and jellies. Now I use strawberry LA to represent DNA clearly. I haven't tried making them double stranded because that would be taking a baking joke too far, but they're going to be the DNA. Marshmallows represent those eight proteins I told you about. Those eight fish-shaped protein proteins and the cleverly sticking out cocktail sticks are the tails that I showed you now what happens in a cell.

The DNA wraps around a group of eight proteins and then you get a little bit of DNA in there and then it wraps around another group of eight proteins and so on, and so on, until you have millions of these groups of eight proteins in our cells and a gene, a fragment of DNA that codes for a protein, will wrap around multiple clusters. Well, that's the basic structure. How does that help us better understand what is happening to our genes? we have current or former professors in the audience, okay, you're going to relate to this, let's imagine it's getting pretty close to the semester, right, and you go home and think I'd like some gin to relieve some stress, okay? ? so you drink some gin and the period goes on what seems endless and you start to discover that you now need two little Gins to relax and the reason you need two little Gins where before you only needed one is because your body is breaking down. reduce alcohol faster, more expression of the gene that breaks down alcohol has been activated and the way it does it is like this, well, not exactly like that, I admit, but yeah, um, this is the gene for breaking down alcohol Just when there is a lot of alcohol entering your system, signals are generated in the liver and little modifications are added to the tails of those proteins cleverly represented by the green jellies, and what those modifications do is basically facilitate the change of that gene.

So they increase the gene expression, let's say the summer holidays come, okay, after a week or two you start to think that you should hit your head with the gin a little, there is no point in your liver continuing to produce large amounts of the enzyme. that breaks down the alcohol because you're no longer drinking alcohol, so the green modifications, the green jellies that basically say turn on this gene, are removed and replaced with purple jellies that basically say turn this gene off, you don't need to be breaking down alcohol right now, so what we have there is a way to turn genes on or off, and it's actually enormously more complicated than that.

Imagine a world where there were like 60 different flavors of jellies and I'm I feel very happy when I imagine that world, so you could have six 60 different colors of jellies in that group and they could occur in all kinds of different combinations, they wouldn't have to. be all green or all purple so you can see. what what and everyonethey could influence expression by different amounts, so you can see that you could start to have a wide range of expression not just intermittently but anywhere in between, okay, so you can introduce enormous flexibility in how genes are expressed, but if We have a situation where we have many purple jellies in many protein groups in the same region, we can also get modifications in the DNA itself represented by the yellow jellies and this says that I mean it.

I don't want to. With this gene turned on, you can get very high levels of that modification in the DNA and when that happens, the whole region of DNA shrinks and becomes incredibly compact and the genes there can never really turn on, so it turns off. genetic expression. permanently from that gene, that is why the genes in our brain, for example, do not express the gene for the house hemoglobin that carries oxygen in our blood, they are clustered in the early stages of development and remain turned off forever, so we can use these types of modifications to change gene expression.

Off Forever due to this compaction or we can also have a more open situation where genetic expression can vary depending on environmental circumstances. All of these modifications are called epigenetic modifications because they are or are not in addition to the basic genetic code and what they all do is change the probability of genetic expression, but they never change the sequence; the gene still codes for exactly the same thing, so it's a fascinating system and it's fascinating in its own right, but it's also fascinating because of the impact that epigenetic modifications have on us. really matter in human health diseases because sometimes they go wrong, we know this happens in certain types of cancer, we have drugs that really help change the epigenetic modifications that are treating certain cancers very successfully and pharmaceutical companies are spending thousands of millions of pounds to We discover more drugs like that, but we also believe that epigenetic modifications go wrong or are set up incorrectly too early in life, for example, can influence many other aspects of human health, particularly things like chronic diseases, like rheumatoid arthritis or type 2 diabetes. where someone tends to be sick for a long time and stays sick and maybe gets progressively worse in those situations, gene expression is becoming more and more deregulated and we think it may be due to epigenetics, but there is one particularly striking example of this inaction. that's being explored and to think about this we have to think about the Jesuits, so I think if the Jesuit said give me a Bo, it's seven o'clock and I'll show you the man and that's actually related in a strange way to one of the The greatest publishing phenomenon of recent years, which is the increase in misery.

Memories. Well, I mean, this is a real photograph of a bookstore. Yes. Tragic life stories. Well, lovely. The most famous example of this is this book called A Boy Named. He was in the New. York Times bestseller list for six six years, okay and there's been a huge appetite for these kinds of books and they tend to follow the same narrative arc: a boy has a terribly neglected and abusive childhood and somehow gets over it and they grow into happy, successful adults and I suspect that one of the reasons these books are so popular is because we actually recognize that those stories are exceptional.

All the sociological data shows that if a child has a terrible childhood, when he is an adult he is at much greater risk of suffering from things. such as alcoholism, addiction to other drugs, suicide and mental health disorders including major depression and also schizophrenia, having a rotten childhood is a terrible start in life and if you tell someone why that is, because it's true even if a child is taken out of that horrible environment and placed in a more nurturing one, they still have a higher risk of mental health disorders in these adults, so you tell someone why that is, why What happened in your childhood influenced what happens in your adulthood, the answer is almost always.

What I understand is that they were psychologically damaged, which is undoubtedly true and completely useless because it is a description, not an explanation. Now we can't prove what's happening at the molecular level in someone's brain, but for someone like me, who is present, I have this strong belief that things have a physical basis and so something must be happening, but we can't do this in children, but where experiments have been done is in a model system which is basically rats, right, baby rats love to be loved, okay, they absolutely love to be loved and when you're a baby rat, the way you feel loved It's just that your mother licks you and grooms you a lot.

Well, there are now mother rats who are very good at licking and grooming and will be very good to all their litters. There are other rap mothers. who are a little irresponsible and do the minimum of licking and grooming and they are like that with all their litters too at this time let's say we take a baby rat that has been very loved and we let it grow well when it is a baby, it is a happy rat and we let her grow and baby rats are not like human babies, it's okay, after a few weeks they will leave their mother rat, they don't sit around waiting for their share of the mortgage, it's okay, there's a lot to say. for baby rats, so baby rats, the happy baby rat grows up and when it grows up you give it a slightly stressful stimulus and the adult rat just shrugs its shoulders, it's whatever rat it is, it's very calm, however, if the baby rat was not licked or groomed. a lot and you let him grow and give him the same mildly stressful stimulus that jumps out of his skin, he is a very stressed adult, so we can see a pretty good analogy with a child who has had a terrible upbringing and who is a stressed adult and if we look at things like the levels of stress hormones in the rats, the ones that were loved as babies, low levels of stress hormones in adulthood, the ones that were abused, so to speak, by not being sufficiently lit and groomed. , high levels of stress hormones very similar to what we see in adults who had a terrible childhood, it depends entirely on whether the babies were loved or not because if you do foster experiments and you take a baby from a litter, a rra baby from a litter Li who was born to a mother who licks in Grooms and you transfer him to a mother who does not lick in Grooms, you get the bad result as an adult, what seems to be happening is that when babies are licked and groomed a lot, they produce serotonin, the happiness neurotransmitter that establishes a particular pattern of epigenetic modifications, specific key genes involved in the stress response, that are established early in childhood, so to speak, and remain there for the rest of the rat's life in the cells of the brain and you get stressed. or a happy adult rat, depending on that initial circumstance, quite controversial but actually quite intriguing research.

Now I'm going to take you to something even stranger here we have on this slide we have a stick insect we have a little fish a quite beautiful salamander in particular lovely kodo dragon, big fan of kodo dragons and a zebra finch, all those animals, in fact, those precise that represent a large part of the animal system can do something that mammals cannot, no one knows what is true? I'm hearing several re yes, I think I heard it there, all of these animals, including the zebra finch, can have a virgin birth, basically that's fine, so still there are female zebra finches that have been kept in captivity and have never been around of a male and yet they can lay eggs that will give birth in life to give rise to live young mammals.

Is it not possible that it is necessary to have a male and a female in the production of madian? And actually that seems pretty simple, we think yes, of course it does, but why, of course, do you and This is one of those examples of an experiment that was designed so beautifully that you think, oh God, that's So obvious, isn't it? Someone once did a beautiful piece of work by Azim Sani in Cambridge in the 1980s and what he did was take a mouse. egg to the right and took out the nucleus and then he would put back into that egg two sperm nuclei or two egg nuclei or one egg and one sperm and the way he did it all of those situations were genetically identical so if you received the egg two egg nuclei or two sperm nuclei or one egg in one sperm nucleus nucleus was exactly the same situation in terms of DNA sequence so I would put the eggs back into pregnant female mice if I used two egg nuclei not live mice If you used two sperm nuclei there are no live mice, but if you use an egg nucleus and a sperm nucleus from live mice because those situations are genetically identical, what that tells you is that the reason you have to have a male and a female when you are doing mammalian reproduction it is because there is something in the eggs and sperm in addition to the genetic information that is necessary for development that information that you must have the additional information is epigenetic information there are particular regions of our genome and it is true for all mammals that come with small epigenetic modifications in Basically they are the yellow jellies in the DNA that say I am from mom or I am from dad and they control particular levels of gene expression that are absolutely crucial to maintaining development, which is why you can't have a virgin birth in mammals.

I have to have epigenetic information from mom and dad. Going on with that is strange work with mice. These are my favorite mice. I don't even know why I have favorite mice, but I do well what you see, there are mice called agouti. viable yellow mice, so we have a skinny brown mouse on the right and this beautiful fat golden one on the left and it's so cute, isn't it? Actually, you also have everything in between. I just showed you the extremes. The strange thing about these is that they are genetically absolutely identical, there is no difference in the DNA code of those two mice, they were raised in absolutely identical conditions, so it has nothing to do with how they were raised, so why are they so different?

It's epigenetic, just a little bit in their genome there's a different pattern of those little yellow gelatinous ones in the DNA and that changes the expression of a gene and as a consequence you can get the thin brown mouth or you can get the fat golden mouse and you can get everything in between with just a few epigenetic modifications at one place in the genome, which shows how significant epigenetic changes can be, but they also showed us something else: fat yellow mice tend to have a high percentage of fat yellow babies and mice skinny browns tend to have a high percentage of skinny brown babies are essentially passing on epigenetic information, so skinny brown mice are passing on skinny brown epigenetic modifications fat yellow mice fat yellow epigenetic modifications until you give them alcohol right now I love the idea of ​​being able to go home at night and you know you walk in and your other half says what did you do in the lab today, honey?

Oh, I have some mice completely given away. I really did it, I was great, I suspect that's how it was. It's not true that this was made in an Australian lab so it's probably a good cut or something but anyway they gave alcohol to the female mice when you do it the fat yellow mice have a different percentage of fat yellow pups and skinny brown mice have a different percentage. percentage of skinny and brown offspring, alcohol has changed epigenetics and that has changed what offspring are like, so all together these bits of information lead us to some really simple ideas.

Epigenetic information is passed from parents to children. We know it has to be like this. otherwise you cannot have mammary reproduction and fat yellow mice tend to have many fat yellow offspring that are passing on epigenetic information. We also know that epigenetic information is influenced by the environment, which is one of the main things it allows us to do. respond to our environment, but the totality of all those experiments that I just showed you lead us to this question: can parents transmit environmental responses to their children using epigenetics? And that's something that was beautifully explored in this experiment again, anyone who is very fond of mice, put their hands over their ears, what did they do, they took mice, male mice, and exposed them to the smell of cherry blossoms and then When they were exposed to the smell of cherry blossoms, they were given a mild electric shock.

I know. someone always says "oh, that point, right" and they did it over and over again and it's just a classical conditioning experiment, so essentially you get to a stage where the mouse learns to associate the smell of the cherry blossom with something unpleasant is about to happen and then it beginsto tremble in fear when exposed to the smell of cherry blossom, as I think it would do, so I took these male mice and allowed them to reproduce, so they looked at their young, looked at their young and exposed them to the smell of cherry blossom of cherry tree no electric shock simply exposed them to the smell of the cherry blossom and they trembled in fear they had inherited the trauma the fear response from their parents and the good thing about this experiment is that actually the groups working on it knew a lot about how smell is detected, how genes are activated using epigenetics in the brain to be able to detect certain smells and what brain cells to observe and they were able to show that that first generation had all the expected changes in their brain cells in terms of epigenetics and gene activation particulars, but so did The Offspring, it's an extraordinary find and it's also completely heretical who is the talk with the incredible sideburns Lamar exactly who is the other animal, yeah, very good, um, as many of you no doubt know.

Lamar was an R for Darwin, he came before Darwin, he was trying to explain how different species were obtained and how different types of inheritance were obtained and the example he gave among many was that the long neck of the giraffe and Lark's explanation was that certain giraffes stretched to reach the highest leaves of the tallest tree and that stretched their necks and then passed stretched necks to their offspring, so it's an example of how they got a longer neck through stretching and passed it on as an acquired characteristic and of course, now we almost laugh at Mark, you know how ridiculous, that's not what happens, we know what happens, it's a Darwinian model.

Some giraffe precursors naturally had longer necks, giving them a selective advantage that they passed on to their offspring. genetic change that basically allowed them to have longer necks, but what I've been describing is the opposite of that, it's lamaran, it's something that happens to the parents, they respond to that, which is an acquired characteristic and they pass it on to his office, so there's a lot of We basically fight about this, but one of the reasons there's a lot of fighting about this, other than the fact that some people are very uncomfortable with the idea that lamaris could happen any time, it's because these experiments must be carried out very carefully and this is a beautiful example um again sorry mice take a little mouse well and put it in a cage with a big mouse and don't let the little mouse escape because it would always run away of the problems, the little mouse becomes more and more traumatized, it stops eating, it gets very nervous, etc., okay, they traumatized the little mice like that and then they mixed them with females and the offspring were dwarfs, okay, and that was interpreted as the male transmitted his trauma.

Okay, he was rty, he passed on that acquired characteristic, you know he was deficient. but then someone did something really clever, they repeated the experiment exactly, but instead of putting the traumatized male M in a cage with a female, they made him watch. I don't even want to think about how you would describe that they got the mouse at home. as a sailor oh I went to a horrible visual place because I got Sean's mouse and they artificially inseminated a female mouse and when they did that all the babies were perfectly normal size, it wasn't that the male had passed on his trauma, which had happened. was that the female, having seen this little dwarf specimen coming, had realized that she was being M with a really poor male.

I think about this when I ordered George Clooney, they sent me Danny DeVito, so once he couldn't see that he had gotten the perfectly normal offspring of the mouse Danny Deito, of course, that shows that it was not an epigenetic transmission from the father to their offspring, which raises a rather more interesting question: how the hell does the female do that and no one knows, we have no idea how? the female manages to restrict the calorie supply when she thinks she has been M with a dwarf male, but it shows how careful you have to be when doing these experiments, now that there is so much science in the field of epigenetics.

I wish I had done it. It's time to talk to you um I'm sure it's of no interest to any of us in this room, but it does play a role in aging, it's not the most important thing, but it does play a role, twins, twins are genetically, you identical twins have the exact same DNA code and yet the older you get the less similar you tend to become and that's because you start to diverge epigenetically sometimes in response to different environments if you have lived different things, sometimes just through random epigenetic drift and it can be very extreme um, if you take identical twins, if one has schizophrenia, there's a one in two chance that the other twin also has schizophrenia.

The more interesting question in some ways is why there is not a 100% chance and that is probably due, at least in part, to epigenetic variation between the twin um tortoiseshell cats with that beautiful black and orange color that is due entirely to a epigenetic effect that actually has to do with turning off a copy of an ex chromosome the female chromosomes in cats um all the T's in shell cats are female if you have a male he is infertile okay it all has to do with how the Epigenetics controls things. um wheat, uh, sorry, not wheat, winter-flowering barley and many other plants need a cold period before flowering, which is entirely driven by epigenetic modifications of different genes in a particular sequence and, in fact, Epigenetics is totally accepted in the plant world, everyone has known about it for years, it's just that it is only us, mammals, who behave as if we have discovered something extraordinary.

Plant people are perfectly comfortable with epigenetics. Who? Dolly the sheep excellent excellent I always have to point out at this point that she is dead in this photo. It's not just that she was the most important sheep in the world, so they just carried her around in a cart. This is after she died and she Royal has it Museum Epigenetics is the reason why it is possible to clone animals. It is also the reason why it is very difficult to clone animals and why clones are often less healthy than adult bees. Worker bees and queen bees.

There is nothing that distinguishes them. genetically, you cannot take the DNA and say which came from a worker and which came from a queen. No one remembers what causes the development of the queen's royal jelly. Absolutely, they are fed royal jelly for a little bit longer, so all that happened in the developing bees was how long they were fed royal jelly, and the phenotypic difference is extraordinary between workers and queens. The most striking example of this is that queen bees have a lifespan approximately 20 times longer than that of a worker bee. If you put it in human terms, we are in the kingdom. of Queen Elizabeth I and we are only halfway through, that is how big the phenotypic changes are and that is absolutely connected to the epigenetic changes in gene expression, so there is all this and much more that unfortunately I do not have time to tell you. but luckily I wrote a book about this and you know what they'll be selling it downstairs, apparently there's a nice person from Blackwells here and they have copies, which is the first one from the Epigenetic Revolution and it just came out.

Three weeks ago Junk DNA was my new book, so what a wonderful moment this is. There are still a lot of things we don't understand about epigenetics and I think that's what makes it so exciting because biology, where we know everything, is terribly boring biology and So all I want to do now is thank you for being a such a wonderful audience.