[Music] it's wonderful to be here at the Royal Institution it's just such a thrill it's fantastic and it's great to have the opportunity to talk to you about epigenetics which is an actually very new field of biology with lots of cuttingedge stuff going on in it but which I love because some of it derived from really straightforward simple questions and I think that's a real Beauty about Modern Biology sometimes so that's what I'm going to talk about I'm just checking the watch because you can't see the clock from here once the lights are down right
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 released there was this huge hoop about about it and some quite entertaining things were said so there was this big press conference and that quote at the top left today we are learning the language in which God created life that was President Bill Clinton now I can't imagine what it looked like for a whole room full of scientists presenting their lives work
to have a politician Rock up and start talking about God it must have been a great moment the one down the bottom is not actually much less overhyped it's from Michael Dexter who was chair of the welcome trust who poured a huge amount of money into this project and he described the sequencing of the human genome as the outstanding achievement in terms of human history now I think we might quibble with that a little um the written alphabet the wheel fire the number zero all of those we could argue have perhaps had a bit more
impact but the human genome sequence is a big deal the human genome our DNA is composed of just four letters but those four letters are used over and over again to create this extraordinary volume which is us and in fact you inherit 3,000 million of those letters from your mother and 3,000 million from your father so three billion letters from each parent and sometimes it just takes one of those to could be wrong and you can have a devastating disease so the genome sequence is really important but it's not all that there is and we've
known that for a long time because we've known of 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 laboratory mice and I have to warn you if any of you are really really fond of mice they come up a lot in this presentation not always in a good way anyway you can imbre laboratory mice and you can keep them under absolutely identical conditions so the mice are so inbred that they're genetically the same as each other and the laboratory 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 such a long time since at least the 1920s that it was given a particular name as a phenomenon it was called intangible variation yeah exactly it's a gorgeous example of where in biology we see something we don't understand it we give it a fancy name and we just kind of park it um a maggot and a fly a maggot and a fly look completely different to one another and yet they
have the same genetic code they must have there's no genome fairy that comes along and gives a maggot a new set of jeans when it pupates into an adult fly crocodiles in mammals it's really easy to understand gender if I were to take DNA from this gentleman here and this lady and I do advise you always get that bit right I did it in a very dark lecture theater right once did awful it never really recovered um but if I was take DNA from these two people and sequence it I would be able to tell
which came from the man and which from the woman because in mammals gender is determined by whether or not we have a y chromosome if I were to take DNA from a male crocodile and a female crocodile I'd sequence it and I'd not be able to tell which came from the male and which from the female because in crocodiles those fabulous descendants of the dinosaurs in crocodiles gender is not determined by gentics it's determined by the temperature at which the eggs develop yes which could be a very odd um consequence of global warming we will
see a skewing in crocodile populations just to add all we other worries right so in all these situations we have scenarios where we have two things which are genetically indistinguishable and yet those two things are different from each other and these are known as epigenetic phenomena basically two things are genetically identical and yet in terms of their phenotype how they look they're different from one another and the word Epi is simply from the Greek and it means at on in addition to as well as so it means there's something else operating as well as the
genetic code now these are all lovely examples of epigenetics but there's one that's even better in fact there's 300 examples of it in this room because each of us we are a masterpiece of epigenetic each of us start from one cell and we end up being formed from about 70 trillion cells just to give you an idea of how big that is as a number if I were to take this lady and to dissolve her into her individual cells which I won't and give them to this lady to count and I say you have to
count one cell a second and when you finished you can go and have a coffee she'd get her caffeine hit in one and a half million years now I love that figure partly because it really demonstrates how complicated we are and partly because about 15% of the audience are now sitting there trying to work out in their heads if I've got the maths right so I can say anything I like for the next 10 minutes it's great so huge number of cells in the human body and with the exception of a tiny percentage of cells
in our immune system all of those cells are exactly the same as each other at 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 another brain cells there we go um and cell types are not only different but they stay different this is why you do not get teeth in your eyeballs I wanted to call my first book no teeth in your eyeballs and my Publishers said it lacked a certain gravitas so we are epigenetic
phenomena and this basically should lead us to be asking the most important question in biology the most important question in biology is always how how can it be that a single DNA genome one set of instructions can lead to so many different outcomes why have I got at least 200 different cell types all from the same DNA code and the way that I think about this is is because DNA is a script it's not a template and you can amend a script and by amending a script like sticking Post-it notes on a script or writing
in pencil Etc you can get different outcomes and I've given examples of that up there two movies separated by about 60 years they use the same script what's the movie very good Romeo and Juliet okay who are the actors in the black and white one Leslie Howard and masir I love u3a that's the first time anyone's got that right right marvelous and who are the actors in the bottom one do you know what it doesn't matter the age when I ever AR this you get I say who are the act and you get Leonardo DiCaprio
you're always in quite High voices right yes Shakespeare script completely different Productions okay and that's what our DNA does that's what we can do with our DNA so what's new well over the last 20 years or so marvelous things have started to happen in epigenetics and the best way I can convey this is using a still from this movie what's this movie time machine very very good um time machine does anyone know that time machine that's up there what um sitcom it appeared in recently relatively recently very good Big Bang Theory excellent good good good
so basically there's a wonderful scene in The Time Machine Rod Taylor who died recently playing the time traveler and at this point in the movie he's only made a model of his time machine and he gathers around his scientific Chums the movie is set in Edwardian times and it was filmed in the 60s so of course all the scientists who come to look at it are all men right so all these BLS sitting around the table and they say to him as the Bea of time traveler how will your time machine work and he says
well the time traveler will sit in that little seat and when he wants to move into the future he'll push that lever forwards and when he wants to travel into the past he'll pull that lever backwards and they all go ah okay as if he's explained it and of course he hasn't explained it all he's done is describe it and so far all I've done for you is describe epigenetics the reason it's such an exciting field of biology now is because we don't just have the description we have the explanations and the explanation are all
related to this now this is what DNA looks like in a Cell though not multicolored famous double helix of DNA but it's not in our cells like a long stringy molecule it's wrapped around eight protein molecules each of those protein molecules is shaped like a fist and there's a cluster of eight of them and what you can see is that there are these tails that stick out from the protein molecules so you've got eight proteins together DNA wrapped around them Tails sticking out now this image represented the culmination of huge amount of work by a
lot of researchers and it cost Millions to generate the data that allowed this picture to be created and it's fabulous but from my point of view of trying to communicate something about science it has some limitations one is that if you're not used to these kind of pictures it's a bit overwhelming whenever I put this picture up I literally can see the audience kind of go woo right so it's a bit overwhelming the other issue with it from my point of view is that it's very difficult to adjust it to show you the things I
want to show you and so I decided I needed an improved version of this so I created one now mine was an improvement because it did not cost Millions I was able to adapt it to show you the things I needed to explain and then once I'd adapted it and I photographed it I ate it um because mine is made from Strawberry laces and marshmallows and jelly tots now I use the strawberry LA to represent DNA clearly I've not tried to make them double stranded because that would be taking a confectionary based joke too far
but they're going to be the DNA the marshmallows represent those eight proteins that I told you about those eight fish-shaped prote proteins and the cocktail sticks sticking out cunningly like that are the tails that I showed you now what happens in a cell DNA wraps around a cluster of eight proteins and then you get a little bit of DNA there and then it wraps around another cluster of eight proteins and so on and so on and so on so you have millions of these clusters of eight proteins in our cells and one gene one bit
of DNA that codes for a protein will be wrapped around multiple clusters okay so that's the basic structure well how does that help us get any further in understanding what's happening to our genes well do we have any present or former teachers in the audience okay you're going to relate to this let's imagine it's getting quite far on in the term right and you go home and you think I'd like a little gin to take the edge off okay so you have a little gin and and term continues what feels like endlessly and you start
finding that now you need two little Gins to take the edge off and the reason you need two little Gins where before you only needed one is because your body is breaking down the alcohol faster it has switched on higher expression of the gene that breaks down alcohol and the way that it does it is like this let's well not exactly like this I admit but yeah um let's this is the gene for breaking down alcohol right when there's lots of alcohol coming into your system signals get generated in the liver and you get little
modifications added to the Tails of those proteins cunningly represented by the green jelly tots okay and what those modifications do is they basically make it easier for that Gene to be switched on so they drive up gene expression let's say it gets to the summer holidays okay after a week or two you start thinking I should really knock it on the head a bit with the Gin there's no point your liver continuing to make large amounts of the enzyme that breaks down the alcohol because you're not taking in the alcohol anymore so the green modifications
the green jelly tots that basically said switch this gene on are removed and replaced by purple jelly tots which basically signal turn this Gene off don't need to be be breaking down alcohol at the moment so what we have there is a way of turning genes on or turning genes off and actually it's massively more complicated than that imagine a world in which there were like 60 different flavors of jelly tots and I'm so happy when I imagine that world right so you could have six 60 different colors of jelly tots on that cluster and
they could occur in all sorts of different combinations they wouldn't have to be all green ones or all purple ones so you can see that what and they could all influence expression by different amounts so you can see you could start having a whole range of expression not just off and on but anywhere in between okay so you can introduce enormous flexibility into how genes are expressed but if we have a situation where we have lots of the purple jelly tots on lots of the protein clusters in the same region we can also get are
modifications to the DNA itself represented by the yellow jelly tots and this says I'm serious about it I don't want this Gene switched on you can get very high levels of that modification to the DNA and when that happens the whole region of DNA scrunches up becomes incredibly compacted and the genes there really can't ever be switched on so it shuts down gene expression pretty much permanently of that Gene that's why the genes in our brain for example do not express the gene for home hemoglobin that carries oxygen around in our blood they're they're scrunched
together early in development and they stay Switched Off forever so we have we can use these sorts of modifications to switch gene expression off Forever by this compaction or we can also have a more open situation where the gene expression can vary depending on the environmental circumstances all of these modifications are called epigenetic modif ifications because they're at or not in addition to the basic genetic code and what they all do is they change the likelihood of gene 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 for us epigenetic modifications really matter in human health disease because sometimes they go wrong we know this happens in certain types of cancer we have drugs that actually help to change the epigenetic modifications that are treating certain cancers very successfully and billions of pounds are being spent in the pharmaceutical companies to discover more drugs like that but we also think epigenetic modifications going wrong or being set in the wrong way too early in life for example May influence
lots of other aspects of human health particularly things like chronic diseases so things like rheumatoid arthritis or type 2 diabetes something where someone is tends to be ill for a very long time and stays ill and perhaps gets progressively worse in those situations gene expression is get getting more and more misregulated and we think it may be due to epigenetics but there's a particularly startling example of this inaction that's being explored and to think about this we have to think back to the Jesuits so I think if the Jesuit said give me a Bo it
is it seven and I will show you the man and that's actually related in an odd way to one of the biggest publishing phenomena of recent years which is the rise of the misery Memoir okay I mean this is an actual photograph from a Bookshop yeah tragic life stories okay lovely the most famous example of this is this book called A Child Called It it was in the New York Times bestseller list for six six years okay and there's been a huge appetite for these kind of books and they tend to follow the same story
arc a child has a terribly neglected and abusive childhood and somehow they overcome it and they become happy successful adults and I suspect one of the reasons why these books are so popular is because we actually recognize that those stories are exceptional all of the sociological data show that if a child has a an awful childhood then as an adult they're at much higher risk of things like alcoholism addiction to other drugs suicidality and mental health disorders including severe depression and also schizophrenia having a rotten childhood is a terrible start in life and if you
say to somebody why is that the case because it it's true even if a child is taken out of that awful environment and put into a more nurturing one they are still at higher risk of these adults mental health disorders so you say to somebody why is that the case why did what happened in their childhood influence what happens in their adulthood the answer you almost always get is they were psychologically damaged which is undoubtedly true and utterly useless because it's a description it's not an explanation now we can't probe what's happening at a molecular
level in somebody's brain but for someone like me who's aign 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 adore being loved okay absolutely adore to be loved and when you're a baby rat the way that you feel loved is that your mother licks and grooms you a lot okay now there are rat mothers who are really good at licking and Grooming and they'll
be really good with all their litters there are other rap mothers who are a bit feckless and do the bare minimum of licking and grooming and they're like that with all their litters as well right now let's say we take a baby rat that's been loved a lot and we let it grow up okay when it's a baby it's a happy rat and we let it get older and rat babies are not like human babies okay after a few weeks they will leave their rat mother they don't hang around waiting for their share of the
mortgage okay there's a lot to be said for rat babies right so rat babies happy rat baby grows up and when it grows up you give it a mildly stressful stimulus and the rat adult just kind of shrugs it's the whatever rat it's very chilled out however if the rat baby was not licked and groomed a lot and you let it grow up and you give it the same mildly stressful stimulus jumps out of its skin it's a highly stressed adult so we can see there a quite good analogy with a child who has had
a terrible upbringing and who is a highly stressed adult and if you look at things like levels of the stress hormones in the rats the ones that were loved as babies low levels of stress hormones as adults the ones that were abused as it were by not being lit and groomed enough high levels of stress hormones very similar to what we see in adults who had terrible childhoods it's completely dependent on whether or not the babies were loved because if you do fostering experiments and you take a baby from one litter a rra baby from
one Li litter who was born to a mother who licks in Grooms and you transfer it to a mother who doesn't Lick in Groom you get the bad outcome as an adult what seems to be happening is that when the babies are licked and groomed a lot they produce serotonin the happiness neurotransmitter that sets up a particular pattern of epigenetic modifications particular key genes involved in the stress response those are set up early in the childhood as it were and they stay there for the rest of that rat's life on cells in the brain and
you get either a stressed out or a happy adult rat depending on that early circumstance quite controversial research but really quite intriguing now I'm going to take you into something even odder here we have on this slide we have a stick insect we have a little fish a rather gorgeous salamander particularly lovely kodo Dragon big fan of kodo dragons and a zebra finch all of those animals in fact those precise ones which represent a huge s of the animal system can do something that mammals can't does anyone know what it is right I'm hearing various
re yes I think I heard it there all of these animals right including the zebrafinch can all have virgin birth basically okay so even so there are zebra finches females that have been kept in captivity never been anywhere near a male and yet they can lay eggs that will give live give birth to give rise to live young mammals can't you have to have a male and a female in madian production and actually that seems fairly straightforward we kind of think yes of course you do but why why of course do you and this is
one of those examples of an experiment that was so beautifully designed that you kind of think oh God that's so obvious isn't it once someone's done it beautiful work from azim Sani in Cambridge in the 1980s and what he did was took a mouse egg right and took out the nucleus and then he would put back into that egg either two sperm nuclei or two egg nuclei or an egg and a sperm and the way that he did it all those situations were genetically identical so that whether you the egg received two egg nuclei or
two sperm nuclei or an egg in a sperm nuclei nucleus it was exactly the same situation in terms of DNA sequence then he would put the eggs back into pregnant female mice if he used two egg nuclei no live mice if he used two sperm nuclei no live mice but if you used an egg nucleus and a sperm nucleus 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're doing mamalian reproduction is because there is something on eggs and
sperm in addition to the genetic information that's necessary for development that information that you have to have the additional information is epigenetic information there are particular regions of our genome and it's true of all mammals that come with little epigenetic modifications on them basically the yellow jelly tots on the DNA that say I'm from Mom or I'm from Dad and they control particular levels of gene expression that are absolutely crucial to maintain development so that's why you can't have virgin birth in mammals you have to have epigenetic information from Mom and from Dad carrying on
from that is some weird work with mice these are my favorite mice I don't even know why I have favorite mice but I just do right what you see there are mice called the agouti viable yellow mice so we have a skinny brown mouse on the right and this gorgeous fat golden one on the left and it is so cute isn't it really is and actually you get everything in between as well I've just shown you the extremes here the weird thing about these is they are genetically absolutely identical there is no difference anywhere in
the DNA code of those two mice they are reared under absolutely identical conditions so it's nothing to do with how they're brought up so why are they so different it's epigenetics just one bit in their genome there's a different pattern of those yellow jelly tots on the DNA and that changes expression of one Gene and as a consequence you can get the skinny brown mouth or you can get the golden y Golden fat mouse and you can get everything in between just by a few epigenetic modifications at one place in the genome so that shows
you how significant epigenetic changes can be but they also showed us something else see the fat yellow mice tend to have a high percentage of fat yellow babies and the skinny brown mice tend to have a high percentage of skinny brown babies essentially they're passing epigenetic information on so the skinny brown mice are passing on the skinny brown epigenetic modifications the fat yellow mice fat yellow epigenetic modifications until you give them alcohol right now I just love the idea of being able to go home at night and you know you get in and your other
half says what did you do in the lab today darling Oh I got some mice absolutely ratted I really did um be great I suspect it wasn't prco um this was done in an Australian lab so it's probably nice shearz or something but anyway gave the female Mouse mice alcohol when you do that the fat yellow mice have a different percentage of fat yellow Offspring and the skinny brown mice have a different percentage of skinny brown Offspring the alcohol has changed the epigenetics and that has changed what The Offspring are like so Al together these
bits of information lead us to some really straightforward thoughts epigenetic information is passed on from parent to child we know that it has to be otherwise you can't have mamalian reproduction and the fat yellow mice tend to have lots of fat yellow Offspring they're passing on epigenetic information we also know that epigenetic information is influenced by the environment that's one of the main things it does it allows us to respond to our environment but the totality of all of those experiments that I've just shown you leads us to this question can parents pass on environmental
responses to their offspring using epigenetics and that's something that was explored beautifully in this experiment again anyone who's very fond of mice put your hands over your ears what they did they took mice male mice right and they exposed them to the smell of cherry blossom and then when they exposed them to the smell of cherry blossom they then gave them a mild electric shock I know somebody always goes oh that point right um and they did this over and over again and it's just a classic conditioning experiment so essentially you get to a stage
where the mouse learns to associate the smell of cherry blossom with something nasty that's about to happen and so it starts to shake with fear when it's exposed to the smell of cherry blossom as I think would I right so I took these male mice and allowed them to breed so looked at their offspring they looked at their offspring and they exposed them to the smell of cherry blossom no electric shock just exposed them to the smell of cherry blossom and they they shook with fear they had inherited the trauma the fear response from their
parents and the cool thing about this experiment is that actually the groups working on it knew a huge amount about how smell is detected how genes get switched on using epigenetics in the brain in order to be able to detect certain smells and which brain cells to look at and they were able to show that that first generation had all the expected changes in their brain cells in terms of epigenetics and switching on particular genes but so did The Offspring it's an extraordinary finding and it's also completely heretical who's the chat with the amazing sideburns
Lamar exactly who's the other animal gir off yes very good um so as many of you no doubt know Lamar was a for R to Darwin he came before Darwin he was trying to explain how you got different species and how you got different sort of inher itance and the example he gave amongst many was that the long neck of the giraffe and Lark's explanation was that certain giraffes would stretch to reach the highest tree highest leaves and that would stretch their necks and then they would pass on stretch necks to their offspring so it's
an example of they got a longer neck through stretching and they pass this on it's an acquired characteristic and of course now we almost kind of laugh laugh at Mark you know how ridiculous that's not what happens we know what happens it's a darwinian model some some precursors to giraffes naturally had longer necks that gave them a selective advantage that got passed on to their offspring the gene 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 happens to the parent they respond
to it which is an acquired characteristic and they pass that on to their offic spring so there's huge amounts of basically fighting about this but one of the reasons why there's a lot of fighting about this apart from the fact that some people are very uncomfortable with the idea that lamaris could ever happen is because these experiments have to be incredibly carefully carried out and this is a beautiful example um again sorry mice take a little mouse right and you put it in a cage with a big mouse and you don't let it get away
the little mouse because would always run from trouble the little mouse gets increasingly traumatized stops eating gets very nervous Etc okay so they traumatized little mice like this and then they M them with females and The Offspring were runty okay and that was interpreted as the male transmitted his trauma okay he was rty he transmitted that an acquired characteristic you know he was a substandard one but then somebody did something really clever they exactly repeated the experiment but instead of introducing the traumatized male M into a cage with a female they got his seen I
don't even want to think about how you then describe that at home they got the mouse of seaman oh I've gone to a horrible visual place for got the mouse of Sean and they artificially inseminated a female Mouse and when they did that all The Offspring were perfectly normal size it was not that the male had transmitted his trauma what had happened was that the female having seen this runty little specimen coming along had realized she was being M with a really substandard male I think of this as I ordered George Clooney they sent me
Danny DeVito right so once she couldn't see that she'd got the Danny deito Mouse perfectly normal offspring of course so that shows you it was not epigenetic transmission from the father to his offspring it does raise a rather more interesting question which is how the hell does the female do that and nobody knows we have no clue how the female manages to restrict the calorific supply when she thinks she's been M with a runty male but it shows you just how careful you have to be when you run these experiments now there is so much
science in in the field of epigenetics I wish I had time to cover with 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 um not the most important thing but it does play a role um twins twins are genetic you identical twins have exactly the same DNA code and yet the older they get the less similar they tend to become and that's because they start diverging epigenetically sometimes in response to different environments if they've lived through 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 will also have schizophrenia the more interesting question in some ways is why is it not a 100% chance and that's probably at least in part due to epigenetic variation between the Twins um torto shell cats with that gorgeous black and orange coloring that's entirely due to an epigenetic effect which is actually to do with switching off one copy of an ex chromosome the female chromosomes in cats um all
T of shell cats are female if you happen to have a male he's infertile okay it's all to do with how epigenetics controls things um wheat uh sorry not wheat winter flowering barley and lots of other plants need a period of cold before they will flower that's totally driven by epigenetic modifications of different genes in a particular sequence and in fact epigenetics is totally accepted within the Plant World everyone's known about it for years it's just that it's only us mamalian types who are behaving like we've discovered something extraordinary um plant people are perfectly comfortable
with epigenetics um who's the Sheep Dolly excellent excellent I always have to point out at this point she's dead in this picture um it's not just she was the most important sheep in the world so they just rolled her around on trolley this is um after she's died and she that the Royal's got it Museum epigenetic is the reason why it is possible to clone animals it is also the reason why it's very difficult to clone animals and why the Clones are usually less healthy than the adults honeybees worker honeybees and queen honey bees there's
nothing to distinguish them genetically you can't take the DNA out and tell which came from a worker and which from a queen anyone remember what causes the development of Queens royal jelly absolutely they get fed royal jelly for a bit longer so all that happened in the developing bees was how long they were fed royal jelly for and the phenotypic difference is extraordinary between workers and queens the most striking example of this is that queen bees have a lifespan about 20 times that of a worker if you put that into human terms we are in
the reign of Queen Elizabeth the First and we're only halfway through it that's how huge the phenotypic changes and that's absolutely connected with epigenetic changes in gene expression so there's all of this and so much more which sadly I don't have the time to tell you about but happily I happen to have written a book about it and you know what they'll be selling it downstairs apparently there's some nice person from Blackwells here and they've got copies of it which is the first one the epigenetics Revolution and just out three weeks ago was junk DNA
my new book so what a marvelous time this is so there is still a huge amount we don't understand about epigenetics and I think that's what makes it so exciting because biology where we know everything is terribly dull biology and so all I want to do now is thank you for being such a great [Applause] audience
