Epigenetics: An Introduction – Dr Nessa Carey

[Music] [Music] so without further ado let's get started with our first talk on epigenetics from dr nasa kerry so dr kerry is a biologist working in the field of molecular biology and biotechnology she's the international director of the technology transfer organization praxis unico and a visiting professor at imperial college london with expertise in the field of genetics and in technology transfer she promotes the movement of science between academia and industry lecturing often to school students and early career scientists dr kerry writes books and articles for a scientifically interested general audience and contributes to the huffington

post she's the author of the epigenetics revolution on junk dna a journey through the dark matter of the genome which explores advances in the field of epigenetics and their implications for medicine you can find out more about dr kerry's work at www.nessusnessacary.com.uk so let's give dr kerry a warm welcome and let's get started next whenever you're ready um good luck and hope you hope you enjoy it thanks very much now um it's great to be here with you all i'm really thrilled to have this chance to talk to you about epigenetics because epigenetics is awesome

it's just weird and wonderful and changing our perceptions of biology all the time it's also massively misunderstood and over hyped and i'm going to try and talk you through some of that so today we're going to be doing this and it's based on my first book which was the epigenetics revolution and niall just gave me a lovely introduction um i actually don't work for practice um anymore and i've just made a note to myself i must update my website i work for myself so i can't claim the glory of that organization anymore but alongside my

serious proper day job i write science books and i like writing them about the extraordinary things that are happening particularly in terms of understanding of dna and of our genome and i actually worked in epigenetic drug discovery for about a decade so it's a topic that i really adore and i hope you're going to enjoy it now i'm going to give this talk more or less in two halves first half is going to focus on what epigenetics is how it works why it's important and then the second half we'll talk about its implications for understanding

psychological disorders and psychological processes so stick with me even if you're really keen on just the psychology bit it'll make so much more sense if you understand the science at the molecular level beforehand so that's what we'll do and we'll have a five minute break where you can grab a quick coffee epigenetics there's kind of a clue in the name it includes the word genetics and we cannot talk about epigenetics without talking about genetics of it and 20 years ago just over 20 years ago first human genome sequence was released and there was this enormous

conference and um at that conference bill clinton who was president of the us at the time stood up and said today we are learning the language in which god created life i have no idea who briefed bill clinton to talk about god in front of a room full of scientists celebrating their greatest step for achievement and a bit of a strange call that one really um but he clearly thought this was a very big thing the sequencing of the human genome part of the cost of that was paid for by the welcome trust the british

charity and the chair of the welcome trust at the time described the sequencing of the human genome as the outstanding achievement in terms of human history which i think resulted in a pudding that was a bit overx it was a very big thing the sequencing of the human genome um but it didn't lead immediately to things like the cure of all diseases which is the sort of stuff that was promised and the reason that scientists promised things like that was because to sequence the human genome was extraordinarily expensive it cost about two billion dollars now

these days you can get your own genome sequence for about a thousand dollars but that's because the technology has accelerated so much back then it was a really big deal but what it was was an infrastructure project a fantastically important infrastructure project we absolutely needed to know the human genome sequence and it's created vast opportunities for loads of other research but it was an infrastructure project it was also an infrastructure project where as a scientific community we were a little bit um probably the right word disingenuous about what it could live because our claim was

that we would understand everything if we knew the genetic sequence and sometimes that can actually be true sometimes the genetic sequence of an individual is absolutely the key thing about them you inherit three thousand million letters of genetic information from your mother and three thousand million from your father and sometimes all it takes is one of those to be wrong one letter in three billion and you can have a devastating genetic disease it can absolutely destroy your life so the genetic code is really important when you have that one absolutely devastating mutation in three billion

letters that's like you've been dealt the worst hand of cards in a game of poker that anyone could ever have and there's nothing you can do about it you cannot win that hand but most of us with our 3 000 million letters of information from each parent we haven't been dealt a disastrous hand we've been dealt a kind of average hand whatever genetics is it's the difference between the hand you're given and the way you play it epigenetics can be the difference between an average hand that turns into a winning one or an average hand

that turns into a losing one now i've used that term epigenetics a lot and i haven't explained what i mean and i will on the next slide because you see even when we were saying we need billions of dollars to sequence the human genome we knew that not everything could be explained by genetics we knew not everything could be explained by your dna sequence and that's because of situations like this what we have here are examples that we call epigenetic phenomena what we mean is that two things are genetically the same and yet they look

or behave differently from each other so a classic example is laboratory mice about 100 years ago people realized you could create identical mice and you just did it by inbreeding you just kept breeding closer and closer more related mice and eventually you'd end up with mice that were all the same at the dna level and yet these mice varied in things like body weight they could have quite significant variations in body weight even though they were genetically the same and kept in the same environment that doesn't make any sense and it was such a well-established

phenomenon that it got given a particular name it was called intangible variation so if you had said to somebody these mice are genetically the same and they're in the same environment why are they different from each other the person would nod very wisely and say ah it's an example of intangible variation which is a classic case of in biology we give something a fancy name and pretend that we understand it and we didn't if you look at a maggot and the fly it turns into they have exactly the same dna exactly the same dna sequence

and yet they look entirely different so the dna is not one dna does not need to one phenotype there turtles turtles are beautiful i love turtles but here's the thing if i were to take dna from a man and dna from a woman i could do some tests on it some very basic genetic tests and i could tell you which came from the man which came from the woman because in humans our sex our gender i never remember which way to get that run right are determined by genetics it's not the same in turtles in

turtles all turtles have essentially the same dna whether they turn out to be male or female depends on the temperature which the eggs incubate and this is a very strange um example of a climate change global warming is causing problems in the ecosystems there are areas of the world where there is now a 50 to 1 imbalance of female to male turtles amongst the hatchlings that's going to have huge effects on the population and so in all of these situations we have situations where two things are the same genetically at the dna level but the

outcomes are different and these are known as epigenetic phenomena and epi just comes from the greek it means at on in addition to as well as so we know that dna is not enough on its own to determine what an organism looks like but there's an even better example of why there has to be additional information and there's actually 132 examples of it on this call at the moment and that is because every single one of us is a masterpiece of epigenetics each of us though we never like to think of this formed when the

egg from our mother fused with the sperm from our dad and it created one cell and that one cell had the potential to become any other cell in it liked at one cell divided into two they divided into four into eight 16 32 and so on until you get to the 70 trillion cells that make up the human body unbelievable number of cells 70 trillion and within those cells we have different types of cells we have skin cells and kidney cells and heart cells and skeletal muscle cells and different types of blood cells hundreds of

different types of cells and yet they all have exactly the same dna sequence as each other the only exception or a small number of immune cells have shuffled their dna around pretty much every one of the 70 trillion cells has exactly the same dna as each other and has that one little starting cell that formed after fertilization so how do we get all of these different outcomes all of these different cell types from the same genetic code it's another example of epigenetics in action and that's because we have to think of dna not as being

a template dna is a script and if any of you ever acted at any point in your life you'll have done the rehearsals that have been a printed script and at some point you'll have highlighted bits of it and you'll stuck post-it notes on it and you'll put pencil marks on it and you'll have subtly modified that script filmmakers do it all the time what i've got here are two examples of the movie romeo and juliet the first in black mice from the 1930s and the one in colour is just before the year 2000 they

both use shakespeare's script they use the same script but the productions look entirely different really sorry about this i'm a bit sniffy today so i'm so happy and that's how i think of epigenetics epigenetics is the process in living organisms by which you can take the same dna script and create different productions which is pretty cool but it's not all there is you see if all i had were cool examples of epigenetic phenomena this talk would be fun but there wouldn't be much real there wouldn't be much science behind it what's new is that we

now actually understand the molecular basis of a lot of epigenetic phenomena and it's the difference between two very important words in the english language this is a movie called the time machine made in the 1960s any of you who are fans of the big bang theory will also recognize the time machine from an episode of big bang theory and there's a brilliant bit where the time traveler this guy here a strangely good looking scientist is explaining to other scientists how his time machine will work and he says if you want to move into the future

you sit in the chair in the time machine you push the lever forwards and you will travel into the future on the other hand if you want to travel into the past you sit in the chair you pull the lever backwards and you will travel into the past and everybody knows as if he's explained it but he hasn't explained it he's described what happens but he has not given an explanation for how it works and in epigenetics now we have some explanations and that's what makes it such an exciting part of science the explanation lies

in this and this looks completely overwhelming this is a picture of what dna looks like in a cell it's been color coded etc but it's a basically a really good representation pretty much everybody knows that dna is a double helix it's this windy molecule but in our cells it's not this sort of long piece of windy string it's actually very structured it's structured around proteins these are called histone proteins and these are really important so you've got these sort of fish-shaped proteins now i don't know if you can see my cursor but if you can

the dna is this double bit this double helix and dna is clustered around eight of these histone proteins to make this nice compact shape but each of those histone proteins also has a little protein tail that sticks out beyond the dna you can see it in some of the views here so what you get are 114 letters of dna wrapped around eight histone proteins and then a little bit of dna carries on and then wraps around another 146 base pairs and on and on and on there are millions of these structures all along our dna

now this was a beautiful piece of work that generated this picture but it has disadvantages from my point of view it cost millions to create the data behind it it's a bit of an overwhelming image if you're not used to these very molecular pictures and also it's really hard for me to adjust this image to show you how things are happening in cells at any one time so i made my own model which had the advantage of it was very very cheap i could modify it and take photos to show you what i want to

show you and then i was able to eat it which for me was a huge advantage because my model is made from strawberry laces and marshmallows and jelly tools and i have to say don't want to boast but i must say this everybody loves this model the only exception was i when i presented it at a particular conference and just as i started presenting it i remembered that this was a conference for people working in the dental sector so if any of you are youth specialists i'm really sorry about all the sugar but it's a

really nice model so bear with me the strawberry laces represent the dna long stringy molecule the marshmallows represent the histones and i've gathered them here in a cluster of eight just like you would have in the cell eight histone proteins and the dna wraps around the eight histone proteins carries on wraps around another eight histone proteins and i was going to make this model much bigger but i discovered my part i had most of the marshmallows so we're just going to stick with two clusters but it allows us to principles now that's what the basic

structure of dna is the great thing about it is it modified think about the current situation we're in we're in a pandemic it's been locked down there's been stress it's been pretty hard and i think it was fairly common that the early stages of the pandemic quite a few of us probably would get to the end of an evening particularly if you were having to homeschool your children and you'd think oh my god that was a tough day i'm going to have a little gin to take the edge off and lockdown continued and you were

still homeschooling your kids and still trying to find past shops and it was all still very stressful and more and more often you'd find yourself thinking i need a little gin to take the edge off but quite soon you would discover that to take the edge off required more than one little gin it might require two or three your body was adapting to alcohol and needing more alcohol to get the same level of buzz here's what was happening in your liver you produce enzymes that break down alcohol proteins break down alcohol and those are coded

for by gene as more alcohol was coming into your system signaling was set up to your liver that said there's more alcohol coming in we need to produce more of the protein that will break the alcohol down and as part of that signaling epigenetic modifications tiny little chemicals were added to the histone proteins near the gene that produces the alcohol breakdown enzyme i've represented those by the green jelly tots and they essentially are giving signals to the cell saying this gene needs to be active we're switching on this gene so it's the green jelly tots

the pandemic continues you continue homeschooling though perhaps it's got to the summer holidays by that point there's more pasta in the it shops to dawn on you that perhaps this habit of having a few gins to take the edge off might not be the healthiest thing to do in the world so you start racking back on the outcome once you do that there's not lots of alcohol coming into the system there is no point the enzyme producing lots of the sorry the liver producing lots of the enzyme to break down alcohol it's just a waste

of resources signaling cascades are set up again the green jelly tops those particular modifications to histones are removed and replaced with a different type of modification which in my case we're using the purple jelly tools because they're my favorites and these are signaling to the cell don't switch this genome we want this gene to be on so you don't produce large amounts of that enzyme there are certain regions in our dna where those what we would call repressive histone modifications the purple jelly tots are there in quite high numbers and they stay there for a

long time and that signals to the cell we really don't want to switch this gene on under those circuits you get even more amendments not just to the histone proteins but directly to the dna itself these are represented here by the yellow jelly tones and those are saying to the cells seriously bone switches genome this gene can stay repressed there are certain areas of the genes where you get really heavy levels of those repressive modifications to the dna itself these are the yellow jelly tots and it gets incredibly heavy covered with yellow jelly tots you

get a vast amount of this modification that says honestly don't switch this genome when that happens it can distort the entire structure of the dna it all gets squashed up like i've shown in this picture and when that happens there is no way that gene can be switched on the dna is completely crushed and you just can't activate that gene that gene can stay switched off for the rest of your life so what we have here is we can take the same region of dna and this is happening all over your dna all the time

and you have a mechanism that acts as an on off switch so the off switch is when you put lots of modification on the dna itself the yellow genetics but you can also have regions of your genome which are switched on but or potentially switched on and switched on to different levels so the epigenetic system is working like a volume control as well as an on off switch i've just used yellow jelly tots to show you the modifications to the dna and purple and green jelly tops to show you the modifications to the histone proteins

in reality there's at least 50 different colors of jelly totally like that can go onto the histone proteins and can create incredible diversity of modifications and that means that you have incred your cells have incredibly fine control over depression so we can switch genes on or off and we can control their volume these modifications are called epigenetic modifications again from the greek because their modifications act on in addition to as well as the dna these small modifications they never change what gene codes for it codes for exactly the same protein but what they do is

they change the levels of expression from a gene so this is where they act as the on off switch and the volume control and this has enormous consequences when a cell divides a particular pattern of epigenetic modifications gets passed on that's how cells once they have become a particular cell type only ever generate more cells of the same cell type so once you've gone from one cell to 70 trillion and those 70 trillion cells are all different types the different types only create and they do that because they pass on the epigenetic modifications so this

is why skin cells only give rise to skin cells this is why kidney cells will only give rise to kidney cells this is why you don't get teeth appearing in your eyeballs i actually wanted to call the epigenetics revolution no teeth in your eyeballs and it's a source of great regret to me that my publisher wouldn't let me um it's epigenetics every cell is inheriting the same dna it's inheriting different epigenetic modifications these modifications in some cases they can go on and they can come off in half an hour and that allows cells to respond

really really quickly to the environment so lots of alcohol comes in lots of alcohol goes out um suddenly um having a large amount of sugar suddenly not having any sugar it allows the cells to respond really quickly to changes that happen all the time all around us because we're in a constant state of flux but epigenetic modifications in some cases can get established and can last a lifetime now that's really important for this thing of maintaining cell identity but it also has health consequences and probably has consequences particularly psychological health which we'll talk about later

and the thing about epigenetics is it provides the link between nature and nurture we always knew genes and the environment somehow communicated with each other and influenced each other we didn't know how it's the putting on and taking off of these epigenetic modifications that allows the environment to interact with genes so this is the physical link between nature and nurture it's also worth thinking how all of this happens and there's a very nice way that's used to describe this so there are enzymes proteins that will put epigenetic modifications onto the histone proteins in the dna

and we refer to these as writers they write the epigenetic code but there are also enzymes that will take these off again and we call these the erasers of the epigenetic code and it's the balance of these that influences what's happening in any one cell in response to the environment and there are hundreds of these writers and readers so again it's incredibly complex system um sorry writers and erasers what i should have said and then we also have readers when these epigenetic modifications get put on to dna or histone proteins other proteins come along and

basically read which modifications are there and they start the next stage in how the cell responds to those changes so we have writers we have erasers we have readers it's a very dynamic system and i think it's fascinating from a biological point of view i think it's amazing we can now understand things like how the turtles end up male or female it's all to do with which modifications get put on but does it matter beyond just the gloriousness which is understanding basic biology well yes it really does but one thing epigenetics can be used to

find new ways to treat diseases this is what i worked on for a decade of my life [Music] there are for example two drugs which are already routinely used in certain types of cancer the one on the left is called fidasa and that affects the yellow jelly tools the ones that go directly onto the dna it affects those modifications and that's used really successfully to control a blood cancer called myelodysplastic syndrome the drug on the right is called salinza this is one that influences much more the modifications to histones that tell a gene to get

switched on so the green jelly tops and this changes part of that process and this is used really well to control a condition called cutaneous t cell lymphoma so both of these drugs target blood cancers the weird thing about these drugs is they were actually developed and shown to work in cancer before anyone realized they were working through epigenetic processes but once people realized they were working through epigenetic processes it triggered a huge number of other drug discovery programs so they allow lots and lots of drugs in phase one phase two phase three clinical trials

targeting other can excuse me other cancers and doing it through attacking the epigenetic system cancer has been a really big topic in epigenetics but actually we now think that epigenetics may be a way of treating other kinds of conditions as well we suspect that lots of conditions may be driven by abnormal epigenetic processes if we think about stuff like type 2 diabetes or rheumatoid arthritis or any of the chronic conditions the ones that tend to develop relatively late in life and then last a really long time we think those might be partly at least driven

by epigenetic processes because there was nothing wrong with that person's dna because it worked perfectly fine for decades but something else has gone wrong their dna hasn't changed and the way i visualize this is imagine you have a bike and it's a beautiful bike and you want to go for a bike ride but you can't because somebody has changed your bike to a bike stand and you don't have the key for the lock if you could just get the key for the log you could unchain your bike and you could go for a bike ride

in chronic diseases whoa sorry my computer's trying to scan right in chronic diseases we see a similar thing happening there's nothing wrong with dna sequences just got locked in the wrong patterns of expression if and almost certainly that has happened through epigenetics if we could find a way of unlocking the epigenetic system in these diseases and creating the right epigenetic signals that would be like unlocking the bike and we could then go and start reversing the condition that would be fantastic oh dear god don't know why mcafee keeps trying to scare my computer i do

apologize so there is lots of work going on in drug discovery to try to treat chronic diseases it may also be very important because we know that many diseases start early this is a theory known as the fetal origins of adult disease that says basically what happens particularly in the first three months in the womb are incredibly important for lifetime long health we know that smoking is very bad for unborn babies we know that alcohol can be very bad for them but we also know that if the mother is um obese that can have long-term

consequences for the baby and their health as they grow up and basically what seems to be happening is that the thesis is responding to the environment it's in the uterine environment and using the epigenetic system to produce certain patterns of gene expression and these patterns of gene expression get stuck and they program the child that they sorry the fetus for how its physiological systems will react as the child gets older so again epigenetics is the point where we might be able to think about new ways of intervening i'm going to continue with that theme of

what's going on in um the fetus by looking at my favorite mice i think these mice are gorgeous these are called the beauty viable yellow mice and extraordinarily the two mice in this photo are genetically absolutely identical they have exactly the same dna as each other and they were raised in exactly the same conditions but one of them is gorgeous it's fat and yellow and it's beautiful and the other one is a pretty typical nice mouse it's brown it's skinny the only reason these two mice are so different from each other is that a particular

part of their dna they have particular epigenetic modifications actually the yellow jelly tops they have particular dna modifications and that dna modification some gene expression and that changes what the mice look like now here's a fantastic experiment that somebody did though i've never understood why they worked on the basis this is a fabulous scientist called them a white law in australia and emma white law knew that if you breed from the fat yellow mice a particular percentage of their offspring are always fat and yellow if you breed from the skinny brown mice a particular percentage

of their offspring are always skinny and brown now that tells you two important things it tells that these mice pass on that epigenetic information that pattern of yellow jets but it also tells you they don't do it perfectly because if they did it perfectly if all of their offspring inherited that same modification then a fat yellow mouth all of her offspring would be fat and yellow and a skinny brown mouse or with her offspring skinny and brown but they're not some of them are in very definite ratios but if you give female mouse alcohol when

she had her offspring it was completely different ratio of fat and yellow to skinny and brown compared with what you'd normally expect so that tells you that actually changing the environmental conditions for the mother changed the outcomes for the offspring epigenetically because this entire phenotype is driven epigenetically it's a really interesting finding and that's very similar to what we imagine when we think about things like fetal alcohol intake so that's that's a really weird situation and actually it was true even if you gave the mother alcohol before she was even pregnant so we're seeing this

effect of the environment on the epigenetics of offspring bear that in mind but let me just segue you something that might seem a little bit different but actually it's fairly related it's something really strange i've put on here some gorgeous animals there's a fantastic stick insect there's a zebra fish there's a rather beautiful salamander there is an absolutely gorgeous komodo dragon i love komodo dragons there's even a zebra finch so what we have here are representations of many parts of the animal system and all of them even controversially the zebrafish can do something that mammals

can't do and that something is parthenogenesis females in these species can create young without ever hated in fact anyone who's ever given one stinky insect will know this because you end up with hundreds of stick insects mammals can't do that mammals cannot ever do parthenogenesis it just doesn't happen in mammals and you kind of need to ask yourself at some point well why not and originally the thought was well it's because you have to have an egg and a sperm they have to come together which is kind of true but more of the description explanation

and here is my absolutely favorite experiment in the whole world this was carried out in the 1980s by a man called azim cerrani at the university of cambridge it seems awesome so should have had nobel prize by now and basically he used the technology of test you baby technology in vitro visualization what he did was he took a mouse egg and he took out the nucleus the bit that contains the dna and then he injected into that empty egg two new nuclei from an age from an egg and they fused and development began just like

you'd normally expected fertilization and he put those we put that fertilized egg into a mouse right into the uterus of a mouse and development continued for a while but weren't completely human and no live young azim did the same experiment but this time instead of putting in two egg nuclei he put in nuclei and again those they fused and development began and he implanted them into the uterus of a female mouse but again development completely haywire no live mice then he did the final experiment he injected in the nucleus from an egg and injected in

the nucleus from the sperm they fused development began implanted into a female uterus and the right number of days later live mice so far so obvious you might think but here's the bit that was really clever in all three of those asians whether it was two eggs two sperm or an egg in a sperm the dna was exactly the same there was no different in the egg plus egg or the sperm plus sperm or the egg prosper but you only got live young if you had the egg nucleus and the sperm nucleus that told you

that mammalian reproduction is not dependent on on dna dna enough alone is not enough to create new mammals you need additional information in there and that additional information is epigenetic information it's modifications tna it's the yellow jelly tots and these have to be passed on and passed on during reproduction in exactly the right way or you can't get human you can't get mammal babies mammalian reproduction is completely dependent on epigenetics there's only certain regions of our dna where these epigenetic modifications need to be passed on um most epigenetic modifications are removed during the production of

eggs and sperm but there are these regions where they have to be maintained and sometimes just one of those regions can be wrong the epigenetic information gets passed on badly when it does that you get really quite severe disorders in humans the lad in this photo has a condition called prada willie syndrome uh huge appetite will overeat enormously severe learning disability the girl in this photo has something called angelman syndrome this is characterized by failure to thrive very underweight but to gain severe intellectual disability and in both cases what has gone wrong is the epigenetics

there's nothing wrong with the dna of these children but the epigenetic modifications have gone wrong so it's a really important mechanism and this leads us to a very interesting hypothesis we know that epigenetic information is passed on from parent child azeem cerrani's expert showed us that in fact they showed that it has to be passed on from parent's child from romanian reproduction to occur but we also know epigenetic information can be influenced by the environment we thought that anyway that emerald's experiments giving alcohol to the mice demonstrated that that is the case so that race

is a really interesting question if epigenetic information has to be passed on from generation to generation and epigenetic information can be influenced by the environment does that mean that a parent's environmental responses can be passed on to their children excuse me quick slugger diet hook zero that would seem like a really obvious prediction that we could make that parents would be able to pass on their environmental responses seems incredibly common sense it is however total heresy it's heresy because it would be an example of lamarckian inheritance so the mark is the guy who came before

darwin and was trying to explain how we ended up with lots of different species and we tend to laugh at the mark these days and think how naive but he was making a genuine attempt to answer a scientifically important question and he gave us an example the giraffe he suggested the ancestors of giraffes were wandering around and trying to get good food and they would stretch their necks to reach the most nutritious leaves on the tree and just like how your muscles get bigger if you work out at the gym your arsenic will get longer

and then it would pass this on to its offspring and this is the concept of the inheritance of acquired characteristics and of course these days we don't accept that at all with the darwinian model which is that just by random genetic variation some animals are better equipped for their environment than others breed at a higher rate of success and they will pass on that favorable dna combination to their offspring and don't get me wrong i am not suggesting for a second that the darwinian model is wrong darwinian model is fabulous beautiful and supported by that

massive amount of evidence just that every once in a while there's a little tweak to it and the tweak is the markian and i'm going to show you a beautiful example of it [Applause] this works a bit better when the slide animates but sadly we've lost the animation but don't worry about it basically start in the top left scientists took a mouse and they expose the mouse to the smell of cherry blossom and then they'd give it an electric shock and you do this over and over again and the mouse learns to associate the smell

of cherry blossom with an electric shock it's a classic conditioning experiment and pretty soon every time the mouse melt blossom it would start to shake with fear as i think i would because it knew an electric shock was coming so researchers conditioned the mice to this situation and then they allowed these mice to breathe these were male mice and in the next generation which is called the f1 generation they expose these mouse and these mice to the smell of cherry blossom and they shook with fear but they had never had an electric shock they had

inherited from their parent their father the fear of cherry blossom and there was no way that this was happening because of mutation because it's happening at a rate massively higher than we would ever see for mutation it was the epigenetic inheritance of a fear response one of the beautiful things about this experiment was the experimenters knew exactly how mice do this in the sense of how they smell certain smells and what it does to their brain and so they knew exactly which cells to look at in the brain and they knew exactly which gene look

at in the brain and they were able to show that once a mountain to the smell of cherry blossom it created epigenetic changes at a particular gene in a particular region of its brain and when they examined the offspring who also had the same fear response they found exactly the same epigenetic changes now this work is incredibly complex and it re this and other experiments like this remain very controversial but in 2017 work was done using tiny little microscopic worms which showed beyond a doubt that epigenetic information can be passed on from parent to offspring

and in the case of these worms through multiple generations particular responses to the environment can be passed on through epigenetic means i think now no one can genuinely argue with whether or not this happens is where how often it happens and how important it is so it's a really important thing and it's something to bear in mind for the next bit of the talk and just before we take a break you can give me three minutes more we will um talk about an amazing case that just rounds up epigenetically how extraordinary this entire field is

and we're going to look at something called rett syndrome red syndrome is a condition that affects girls which is a really heartbreaking condition for the families at first the little girl will seem to be developing perfectly normally she'll meet all her or her normal developmental life milestones but then from about 12 months on she starts going backwards begins to lose those responses so loses any language skills that have developed um develops very repetitive hand actions has quite severe intellectual disability and it's essentially a very very extreme form of autism this incidentally is probably where some

of the fear about vaccines for mmr and autism developed is that parents saw that their child had been doing fine and then stopped doing fine and they associated it with the vaccines the reality is that these symptoms developed about the same age that vaccines are usually administered so it the two things weren't causative they weren't related to each other so rett syndrome it's a very heartbreaking condition and it's caused by a muta by a mutation so these girls have got a dna sequence that's wrong but the dna sequence that's wrong codes for one of those

readers remember i told you earlier in the talk about proteins that will bind to epigenetic modifications and trigger the next set of signals what in these girls it's in a protein that binds to the yellow jelly tops the modifications to dna itself so those epigenetic modifications are laid down fine but the girl's cells can't read now there's a guy called adrian bird ordinary scientist works at the university of edinburgh and he created mice that have the same mutation as the girls have who have ret syndrome for those who like gene names this gene is called

mecp2 and these mice he allowed them to develop but the really class was that the mice could grow up having rhett syndrome essentially they could have this mutation in the gene so they couldn't read epigenetic signals but then he'd switch on an active version of this gene and here's what happened i'm going to show you the mice now i'm going to do this via a video so this is a mouse that basically has rhett syndrome whoa nile seem to have love is it coming yes okay here's a mouse with threat syndrome it's been plunked down

in the middle of a tray and it's just sitting there that is very uncharacteristic for mice in fact if the camera wasn't shaking you'd barely know that this mouse was actually there or rather this was being filmed so the mouse just sits there doesn't explore doesn't do anything and when it's picked up it just dangles in the air it just hangs there so that that's a mouse with right syndrome now let's see if i can get back to the other one okay what i'm going to show you now in a moment is that same mouse

not just a mouse from the same experiment but actually the same mouse and this mouse it's had its genes switched back on and it is extraordinary let's just get this up not going to panic no panic from me no siree aha here we go so this mouse plot down same one as we saw earlier it's wandering about it's having a look now it's gone to the edges of its box as you would expect and it's rearing up on its back legs anyone who's watched a mouse go along the skirting board will know this is typical

mouse behavior it's inquisitive it's curious it's wondering what's going on it's having a look around it fancies exploring the world in a moment a hand is going to come down and it lifts something else and it doesn't just dangle there it sticks its legs out which is typically what mice do in those experiments what adrien bird has demonstrated is that even if the brain has developed with this complete breakdown in its epigenetic system leading to totally abnormal behavior if you can reverse that molecular problem in the brain the mouse goes back to normal imagine if

we could do that in the girls with ret syndrome that these children could just resume their developmental pathways this is the first experimental indication by the way that intellectual disability could be overcome that's an extraordinary concept we can't do that yet we don't have drugs that will enable us to do in humans what adrian was able to do in mice using genetics but it indicates that it's feasible and it makes it worth trying to create those drugs that's extraordinary reversal of intellectual disability i'm going to make you think about a publishing phenomenon that was really

big especially a few years ago and it literally used to be possible to walk into bookstores and find a section called tragic life stories and probably the example that was most famous for this was a book called a child called it by dave peltzer which was on the new york times bestseller list for something like 76 weeks something insane and these stories all followed a very similar arc a child had a terrible abusive neglectful upbringing and somehow overcame adversity and became a very successful adult and i always found a bit of an ick factor in

these books i didn't really get involved with this genre i found it a bit voyeuristic but they were incredibly popular and i think part of the popularity was because of the happy ending but i wonder if behind that the reason that these were so popular was because somehow either consciously or unconsciously we knew that the happy ending was the exception and therefore we were reading about exceptional people because there are sadly vast amounts of data that demonstrate that happy ending is not the norm now i've just put one reference up here from the one that

i picked at random but there is an enormous body of literature demonstrating that if a child has a terribly abusive or neglectful upbringing they are at significantly higher risk of physical conditions such as heart disease and autoimmune disorders but also in terms of what we call psychological or psychiatric conditions so they're much higher risk than the general population of depression alcoholism other forms of addiction extreme anxiety suicide etc basically having a lousy start in life is incredibly damaging for the adult and this can be the case even if the child was removed from the abusive

or neglectful environment um if they were then say adopted or into a very loving and caring family they are still at risk of long-term mental health problems and we take that as uh basically as read but why should that be the case why should something that happened somebody when they were seven still be having really negative consequences for them when they're 57 you know they're in a completely different environment why why are they still trapped in a high stress response to their world and when you ask somebody that the response is usually well the child

recycle the this individual is psychologically damaged as a child and that damage has persisted into adulthood and that is all very well but it's a description it's not an explanation it's just telling us what we already know but rephrasing it in a different way what's the molecular basis for this because to somebody like me who is a biologist i'm a big believer everything will have a physical basis because for me concepts like the soul or the id or personality they have to have a physical basis somewhere or for me personally i don't know how to

engage with those concepts so let's see if we can think about how that would happen and there's a very good working hypothesis when a child is going through trauma and stress there is a stage where all their brain responses are still very plastic they're very very they can still respond in particular ways to their environment nothing's become particularly hardwired and the idea is that in response to the stress and the fear certain pathways get over activated in the brain others get repressed and they're basically an adaptation to allow the child to deal with the situation

they're in typically they're associated with fight or flight responses but that if these are established at a particular time using epigenetic modifications they can get stuck and those epigenetic modifications remember i told you some of them could be incredibly stable so they remain in place in the genes in the brain keeping the brain in trauma response mode even if the child is no longer in a traumatic condition even if 30 or 40 years passed it's a very good very attractive working hypothesis but the problem is it's extraordinarily difficult to investigate and you certainly can't do

it in humans even if we left aside the logistical issues the ethical issues are completely overwhelming but you can investigate this in rodents and that's what people did and here's one of the experiments now basically rat babies like to be loved and the way that a rat baby feels loved is if its mother licks it and grooms it a lot when it's very young baby if a rat baby is licked and groomed a lot when it's little it's quite a happy baby and it's quite relaxed and you then take the rat baby the rat babies

leave their mothers after a few weeks you know rat babies do not hang around for 30 years hoping to help with mortgage it's quite natural that they leave their mother and if a few months down the line or a year down the line you take that same rat baby and you expose it to a mildly stressful stimulus rat baby is like the one in the bottom left there this adult doesn't care if you give it a mildly stressful stimulus it just kind of shrugs it's the whatever rat it's very chill however if you take a

rat baby and its mother is a bit of a feckless mother and the baby doesn't really get much licking or grooming that baby starts to become quite stressed now again after a few weeks it will leave its mother and if the same period of time later a year or whatever you give that rat baby a mildly stressful stimulus sorry the rat adult mildly stressful stimulus it jumps out of its skin it's on the ceiling with stress it is a highly stressed adult rat what happens in those rats is if the baby is licked and groomed

or not which is how it experiences what we would think of as love it's very relaxed and it produces a large amount of the neurotransmitter serotonin which is the happiness one sorry i have to hit zero again the serotonin sets up signaling pathways in the brain and you get a particular set of epigenetic modifications to the histone proteins um basically like the green jelly tots and they're on certain genes in certain brain cells and they stay in position on those genes in those brain cells and what they do is they dampen down the whole fight

or flight response because this rat baby is in an environment where actually it doesn't need to be terribly stressed on the other hand if it's a rat baby that hasn't been lit and groomed a lot it doesn't produce much serotonin and you get a different level and different types of epigenetic modifications on the genes in its brain and the effect of these epigenetic modifications is to drive up the stress response um and to make the animal just more more of a hair trigger in terms of how it reacts to the environment basically it's always expecting

something bad to happen and so it responds really explosively to anything negative this is all to do with what's called the adrenaline cortical axis so cortisol is a hormone which is produced in response to stress if you look at the chilled out rat babies when they're adults their cortisol levels are quite low but if you look at the adults that haven't been licked and groomed as babies their background cortisol levels are high they're always expecting something stressful and actually we see that in adults who had very neglectful or abusive upbringings as humans so we can

see that there is a very nice model here for why early childhood trauma could become hard set as an inappropriate fight or flight response for later adult life with all the consequences that has for things like anxiety and addiction as a means of self-medicating etc it's probably tempting to think well if we understand the physical basis of it the molecular basis why don't we create drugs why don't we create drugs so that we can treat those children so that they don't go on to have the ethical sorry to have the adult trauma and there are

various reasons why we can't one is that it's far too complex the human brain this is one of those expressions i got from someone i love it the human brain is the most complex 1.5 kilograms of material in the universe billions of cells making literally trillions of connections and although this epigenetic model is a nice one it's pretty unnuanced compared with the complexity of the human brain and we really wouldn't know how to create drugs that just target these few maladaptive epigenetic modifications so it's much too complex to do biologically with our current understanding also

remember that the maladaption is only a maladaption when the child goes into a more stable environment they're perfectly adapted for a really bad environment when these are the modifications being established it would also be too expensive because what you'd have to do is you'd have to treat children when they were say seven years old and then follow them in clinical trials for the next thirty years that would cost gazillions no no drug companies that can do this a very important question is we don't know who to treat you see you could have a hundred children

in very similar environments and only a certain percentage of them grow up to have the mental health conditions as adults and we don't know which ones and we don't know why and it's probably a complex combination of genetics and environment and chance so we would be treating a whole cohort of children without actually knowing which ones really need the drugs and which ones don't that's a very dodgy thing to do but the other reason why i think we should never do this is because we know how to prevent this from happening we need children to

have safe supportive environments and we would be using pharmaceuticals as a means of trying to avoid creating the equitable just society that we know that children need to thrive so this is why there is no work on these on creating drugs to treat this but it is a really really interesting way of imagining why adult trauma persists from childhood trauma it may also not just be in childhood that these things happen um epigenetic maladaptation is an intriguing hypothesis another example we might think of is post-traumatic stress disorder if an adult suffers a very traumatic event

why do they keep having flashbacks what gets hardwired into their brain that means they are still responding to an event that isn't even happening anymore we could also think about epigenetics and depression if you've had one episode of depression you are much more likely to have another one than the general population why maybe the brain is getting epic its epigenetic baseline is changing maybe it's making you that bit more prone slipping into a depressive state next time there are lots of reasons to think epigenetics might be involved in depression um one of the reasons is

because the drugs that treat depression most successfully for most people selected serotonin reuptake inhibitors they change your serotonin levels really quickly but you don't start symptomatically improving for several weeks that suggests that maybe there's a longer-term process that has to go on which may be involved with the removal or the re-establishment of certain epigenetic modifications so there's really good reasons to think epigenetics might be involved in psychological and psychiatric disorders but testing that is unbelievably difficult and if we find epigenetic drugs that work in some of these disorders it may well be that we find

them by accident the same way we did with some of the cancer drugs something that's even harder to test and yet is an area which gets so much coverage in the popular press people adore this area is the area of um transmission of epigenetic trauma and i cover this because people love this concept and it is probably a tangible example of thomas huxley's statement of many an ugly hypothesis has been slain by a beautiful fact so we'll talk about this a bit it's a very seductive idea let's think back to those mice from before the

coffee break the ones that had definitely inherited trauma responses from their fathers in response to the smell of cherry blossom one set paper came out i started getting loads of calls from people working in psychology and psychological conferences asking me to talk about this and saying because all our members are so excited because they realize now that this can explain why somebody who objectively has a nice life is struggling maybe they've inherited epigenetic trauma so it's a very seductive idea why am i so depressed when life is objectively very good and then you can prove

these patients and maybe it turns out dad and granddad were traumatized in world war one and world war ii other way around sorry about that um and that this individual has inherited their response to trauma it's a very appealing hypothesis and i do understand why it's so seductive but the thing to remember is that there is very little evidence to support this claim it's an area which is enormously hyped and receives a great deal of attention and it's very controversial um this was one of the ones that got a huge amount of coverage which was

basically saying that the children of adults who survived the holocaust had epigenetic changes which they had inherited from their parents and which made them more psychologically fragile and there was so much wrong with this paper for a start the epigenetic changes were not the same in the in the parents who had been through the trauma and their children they were very different changes but it was just a claim that these were different compared with the rest of the population um it's also that it worked from the basis that what they call psychophysiological trauma is inherited

now that's a very difficult thing to unravel because of course for someone who's been through something as unbelievably traumatic as the holocaust it's probably quite likely that affects that individual psychologically that will have different effects on the tension in a household for example and in a family and in the way that a family is raised and actually that's incredibly important to remember is that what you might be seeing is just a change in behavior and that that is then influencing the child and that that change is itself reflected in the epigenetics it does not mean

the epigenetic changes were automatically passed on as epigenetic changes to the child now one of the few ways that you could investigate this would be through adoption experiments you remember that rats that i showed you earlier the chilled out rats and the stress rats well in those experiments because they have rats the experimenters were able to do the experiment of switching babies rats from one mother to another and they could show that the final phenotype of the rat was totally due to their early nurturing experiences nothing to do with genetics or anything else like that

so there you could show that it was absolutely an environmental response and what we might be seeing here is in children of people who have been severely traumatized maybe there's a psychological response to growing up in that household i'm not implying for a moment that parents who've been traumatized make bad parents i'm just saying it's different and papers like this get an enormous amount of coverage and it's so frustrating because actually the data themselves are fairly weak so my advice would be every time you see a paper like this be a bit skeptical so does

epigenetic inheritance in humans does it happen well in reality it probably does sometimes um it's most likely i suspect to occur in response to things like diet um and there's certainly good data from animal systems that this is happening so it may well be that epigenetic inheritance does sometimes happen in humans problem is we'll never prove it certainly not for an individual we can show at a population level that we get epigenetic changes and that these are often in response to things like diet but again we show them at a population level in the same

way that we know if a cohort of children has been traumatized that a certain percentage of them are likely to have adult health mental disorders we can't however say which of those children will have grown up to have adult health disorders and so therefore it's incredibly difficult to demonstrate epigenetic inheritance in humans and it's because we're a lousy model system it makes it incredibly difficult to pick out the signal that says yes we are psychologically and epigenetically influenced by what happened in previous generations so it's worth spending just a little time to think about why

we're so different so model systems mouths those little worms that i told you about rats etc they can be great because you can create experimental groups that are all genetically the same you take out all the variation that could be caused by dna changes can't do that in humans our genetics is incredibly diverse so that makes the data really messy um with the mouth systems you can make sure that all the mice or all the rats or all the little worms all have exactly the same environmental experience you can standardize that as much as possible

you can't do that in humans we all have massively different environments also what you can do with the model systems you can create a really simple environment and then give them one massive stimulus and look for any effects of that stimulus we're not like that as humans we live in these incredibly complex environments and most of the environmental stimuli that will come at us are fairly small so we can't do this thing of a very flat base iron then one massive event doesn't happen most of the time in humans also these model systems have the

enormous advantage that they have loads of offspring and they have them pretty quickly humans we have small numbers of offspring and we tend to take a really long time about it so yeah we're a terrible experimental system so it's not easy to unravel if this stuff works in humans but you know what even in the mice you can get really misleading experiments i always tell people about this one because it's such a beautiful example of how this work can go wrong so um i have to say mice have a bit of a rough time in

the labs of epigeneticists but i've gotta admit this is also really interesting science um experimenters did a set of research where they traumatized a male mouse and the way that they did this was they basically left it in a cage with a bigger mass now mice are cowards if a mouse is outgunned it just basically runs away if it can't run away it keeps getting bullied by the bigger mouse and the little mouse really gets quite into a state of despair it doesn't eat very much because half the time you can't get to the food

stops grooming properly so it ends up in really bad condition it's this horrible little specimen of mountain on monday the experimenters took this poor little mouse that's all scruffy and underweight and they dropped it in a cage with the female who was ready to breed so lucky day for our trauma and her's mouse and he bred with the female and then he got taken away again and the female gave birth to a litter and all of the offspring were really runty they were really small compared to the size mice should be and this was in

interpreted by the group who did the experiment as the male males had passed on his trauma so it was an epigenetic transmission of trauma another group looked at the data and thought hmm i wonder so they did the experiment again with one really important exception at the bit where they picked out this traumatized male mouse and he had been dropped into a cage with a female who was ready to breed instead of doing that they didn't take him to the female they just got the semen out of him i have no idea how you go

home from work and explain that that's what you do for a living but anyway they got the semen out and they artificially inseminated the female and when they did that she gave birth to a litter and the litter were all of normal size they weren't raunchy at all the male had not epigenetically transmitted his trauma what had actually happened was that this female had seen this pathetic specimen of mauston coming to water and somehow or other had thought ah i suppose if i have to i might as well but i'm sure as hell not going

to put a large amount of nutrition into this litter because seriously look at this book and maybe i'll have another chance with another male and i don't want to have used up all my energy on this one litter from this frankly quite substandard mouse um i try and put this into human terms and the version i usually come up with is i ordered george clooney they sent me danny devito it's that level of disappointment so this was not epigenetic transmission of trauma this was a female controlling the amount of nutrition to her offspring and the

really cool thing is we have no idea how she does it absolutely no idea at all it's amazing but it does show you just how careful you need to be running these sorts of experiments about epigenetic transmission of trauma even in a model system so that gives you some idea of how difficult it is to do and to detect in humans but if it does happen if we can if there is epigenetic transmission what's the implications of that and if there isn't what are the implications of that should we be happy or sad about it

well i always caution about people using epigenetic transmission as a get out of jail free card i don't think it works like that i don't think you can sit there and say the reason i am 32 stone is because my grandad liked having a doughnut on a friday that's not how it works so on the one hand we can't use it as a clear card but on the other hand it also means maybe we could liberate ourselves a bit from some of the guilt of what we're doing to our descendants you know god knows women

who are pregnant and who are mothers have enough pressure on them already about all the things they should be doing to make sure their child is healthy parents shouldn't necessarily be worrying again that they had a doughnut just before they had sex and conceived their child because again it's probably not that you've ruined that child's life by one epigenetic activity the majority of things that are important to us as humans that really affect our health are the things that we do ourselves they're the decisions that we make ourselves and how we enact on those so

i think yes this doesn't liberate us from feeling guilty about what we do but it does liberate us from feeling guilty about what we're doing to our descendants and actually guilt's not very helpful anyway so i don't think we should feel sad about this um i think epigenetics frees us from genetic determinism in many cases but i don't think that means we should replace it with epigenetic determinism because humans are just too complex it doesn't work that way whenever you read anything about epigenetics i would caution you to remember a few things and that is

that biologists always make mistakes it's in the way we trained and it's not to do with making experimental mistakes it's how we interpret the data we are always trained to think the first thing we discover is the most important um probably about 80 percent of drug discovery for example in epigenetics is going into one particular class of epigenetic proteins and we have no evidence that really tells us those are the most important it's just that we discover them first and so we know most about them and so then we keep funding research on them and

then we publish more papers on them and then everyone says you see those were definitely important we told you so we always make this mistake we do a sort of founder fallacy if we don't know what something does we assume it does nothing for a very long time people said the epigenetic system wasn't important it didn't do anything seemed rather unlikely but that was the assumption when i created my model of the gemitots um with the two clusters of histones and a bit of dna in between what i left off is that there is a

histone on that dna in between and for a very long time everyone said it was really unimportant simply meant we didn't know what it does we now are starting to realize it's probably very important in certain processes i mean otherwise why would your cell make millions and millions and millions of copies of i think but we just go no you don't know what that does therefore it doesn't do anything epigenetics drives me mad because people just spend their entire time arguing about their definition of epigenetics if you get five epigeneticists in a room you will

get five different definitions of exactly what the term means i actually don't care we should just talk about the biology we should also never talk about pathways really i do because it's simpler and that's how i've been trained and every biologist i know does but cells don't work in pathways they work in very complex networks um it's the same reason why there's no point saying what comes first nothing comes first everything's working in these and we also pretend that cells and systems abide by our boxes and if they don't fit into our categories we say

well there must be something wrong with that science it hasn't fitted into our categories at all that's ridiculous that means our categories are wrong that's the one fallacy i didn't used to fall for some reason um even when i was a kid and people told me bumblebee shouldn't be able to fly you know i used to think well that's ludicrous they're flying there's something wrong with your theory um so we need to be very wary that we put up these nice divisions and then we say the science is wrong if it doesn't fit into the

divisions it's probably more that our divisions are wrong and the worst mistake you can ever say in science is that can't happen um epigenetic transmission of information between the generations oh my god richard dawkins fanboys go bananas about that one because in hardline darwinian speak that should never happen um i would say darwin was the premiere amongst all data driven scientists absolutely darwinian mendelian systems almost always right but just occasionally there's a little tweak to it it's the epigenetic system live with it um things remember genetics and epigenetics work together there is no point saying

things like which is more important if either of it is wrong there are bad consequences um also association does not imply causation you may see an epigenetic change it does not mean it was caused by a particular environmental stimulus or that it causes a particular response and the problem is in biology these days we now are able to process enormously huge data sets and we can find correlations but it doesn't mean that they are biologically significant or even that they are related there's a fabulous website which is one of my favorites when i'm bored i

go to this website it's a website cited curated sorry it's furious correlations it's brilliant go to it if you ever fancy just seeing how much association does not imply causation in humans most epigenetic effects will be subtle and they will be lost in the background this is not something to worry about significantly it's just adding more detail into phenomena that we already knew about but now we're starting to understand how they happen and although i mock the richard dawkins bad boys and the skeptics about epigenetics and about epigenetic transmission of information between generations i think

it is absolutely appropriate that the more revolutionary the concept the greater the burden of proof we should have to prove really stringently that these things are happening now i could if some lunatic gave me free rain give you an entire day on epigenetics easily because it covers so much that's fantastic about biology um epigenetics is really important in plants for example um things like winter winter stone barley and the fact that it won't flower unless the seeds have been in the ground during the winter that's completely due to epigenetics and transmission of epigenetic information happens

in plants all the time between generations and plant biologists can't understand why animal biologists are so irritated epigenetics plays a role in aging it's probably not the only factor but it definitely plays a role um identical twins identical twins are genetically identical obviously they're not epigenetically the same and as they get older they get epigenetically more and more dissimilar to each other and this may be part of the reason why you can have a situation where one twin for example develops schizophrenia and the other's perfectly healthy tortilla shell cats or tortoiseshell cats are female well

all fertile short shell cats are female um and we don't have time to go into it but if epigenetics wasn't a process in ourselves 50 of people on the planet wouldn't exist because epigenetics is essential for females to be able to develop we have two copies of an x chromosome men only have one and we switch one of ours off epigenetically and it's vital we can't survive we don't um this sheep is dolly the sheep the first cloned mammal um i always point out at this point that dolly in that photo is dead she's being

reeled to her case in the royal scottish museum it wasn't that she was so grand she just refused to walk in anywhere anymore epigenetics is the reason why cloning is possible it's also the reason why cloning is very low efficiency and my favorite example is honey beans honey bees if you sequence dna from a queen honeybee and a worker you can't tell which came from the queen and which from the honeybee air which from the worker and that's because they're genetically essentially the same as each other the only thing that turns a queen into a

queen is that she is fed royal jelly for longer as a grub and that causes enormous changes in her body and her physiology and those changes are involving epigenetics and maintained by epigenetics and to give you some idea of just how extreme a difference you can have in phenotype because of epigenetics a queen honeybee will live for about 20 times as long as a worker if you put that into human terms we are halfway through the reign of queen elizabeth the first it's an enormous change and epigenetics plays a role in that so epigenetics it's

fantastic it's marvellous approach it with a bit of skepticism and we have 20 minutes left for questions which i think is what nile told me to aim for so apologies again about the technical glitch and thank you so much for your attention and please get the questions coming thanks very much for having me and talk there i think people really enjoyed that i think it was really accessible as well um so we've got we've got about maybe seven or eight questions here people have asked um some through them one by one okay so the first

one is from lauren and she's asked do you know of any labs working on autoimmune diseases like multiple sclerosis if not which are working on rheumatoid arthritis and is there any way we can conduct epigenetic gwas to identify specific patterns in patients great thank you very much it's a great question so the last bit is about what we call g bus scores which are gene sorry g west which is genome-wide association schools and basically we know if you look at dna in individuals with and without certain diseases that you can show there are certain combinations

of genetic sequences which make us more susceptible to a disease um the difficulty with things like multiple sclerosis and lots of other these conditions is that there may be a hundred different sites in the genome all contributing one percent of the risk but often what we don't know is why those contribute to the risk and we think one of the reasons might be because depending on the sequence you may be more or less prone to get epigenetic changes at that sequence which can tip you towards gene expression that leads to these disorders so there's that's

a lovely example of genetics and epigenetics working together there are some labs working on this lauren um can't remember the names of the ones that are working on autoimmune diseases at the moment but very happy to look them up there are certainly labs that are looking for these associations the difficulty is converting these associations into meaningful biological data that we can actually intervene with and you also have to be very clear that what you're seeing is a genuine biological signal not a response to something else and the reason i say that is there's been a

really nice piece of work done with chronic obstructive pulmonary disease trying to find an epigenetic signal associated with developing chronic constructive pulmonary disease and the lab found a signal and luckily they were a very smart lab and it would have been really easy to publish this and say aha in people with chronic obstructive pulmonary disease they have an epigenetic change at this position in their genes and that is triggering chronic obstructive pulmonary disease actually that wasn't what was happening the epigenetic change they saw is one that happens in response to smoking and smoking is a

known major risk factor that for copd so they couldn't demonstrate that the epigenetic change they found was driving the biology of the disease it may just as easily have just been a response to smoking and the smoking was driving the disease by other roots so you have to be incredibly uncareful how to unravel these one of the areas i think as well that we're going to start seeing a lot more work on and the data are just starting to emerge there are data suggesting that childhood trauma and neglect basically make people much more susceptible to

autoimmune conditions and this relationship between the neurological system and the inflammatory system is one we're only just starting to unravel and epigenetics is another layer of computation on that um one thing i should probably warn you all for it's almost every question you ask my answer will contain various details like that and basically come down to it's all really complicated and none of it's black and white there's loads we don't know about epigenetics so i apologize in advance for the fact that will be essentially my answer to almost everything but that's because that's the reality

okay i like the disclaimer um gita has asked are there any inputs on uh type 2 diabetes reversal she's interested to know um again it's not something that we have a great deal of information about at the moment the problem with this situation is that with something like type 2 diabetes we have very poor understanding of everything that's going wrong in type 2 diabetes and again what you have to discriminate between is data and information so it would be fairly easy for example to take blood cells from people who have type 2 diabetes and compare

the epigenetic signatures or the epigenetic patterns that you see in there from people who don't have type 2 diabetes the problem is that that might just tell you that actually people with type 2 diabetes have a particular range of epigenetic they get epigenetic changes but those could be in response to the type 2 diabetes they may not be driving it and this question of how much epigenetics simply reflects what's been happening as opposed to how much epigenetics predicts what will happen next and controls what will happen next that's a really complex one so there are

labs working on it there are definitely pharmaceutical companies trying to use this approach but it's very early days unfortunately what we do know works in type 2 diabetes is if you're able to have radical enough alterations to people's lifestyle we know that that can actually have a spectacular effect on type 2 diabetes but of course that's really hard work and for various reasons it's very difficult for a lot of people to do i do think there is a question around the extent to which with a lot of conditions we decide on a pharmaceutical approach rather

than a lifestyle approach okay that's a great answer um the next question is from alexandra and she's asked are you familiar with the research on highly sensitive people and animals apparently they tend to be worse worsely affected by childhood trauma but it looks like they're more robust than nonsense sensitive members of the species if they received good parenting uh no i'm not particularly to be perfectly honest um i was going to try and black my way through that one but actually maybe try and come back for me with it i'm really easy to find on

social media um if you just go to my website you can find an email address that you can link it to so i'm not even going to try and blank my way through that one sorry i think honesty is always always best policy here um okay the next one is from hal um what is your take on yehuda's 911 study where her tech was her having tested all the pregnant women in or within the close vicinity of the world trade center and the fetus's low depleted cortisol levels in the first trimester and then brackets um

low depleted lower depleted cortisol levels being one of the symptoms of ptsd supposedly yeah um okay so don't want to be too critical um but i think i think there's a real quest for easy answers that is not going to play out well um because human psychology um do we really feel that somebody's psychology can be entirely explained for example by their cortisol levels um we one of the problems that we have is we don't even have the right terms to discuss most of these things we don't know a biological basis to most human psychology

even when we take something as overt as depression one of the reasons why it's incredibly difficult to develop new drugs for depression is because we have no animal models of it so that makes it hard to do i think it's really really difficult to interpret these studies well we certainly know that stuff that happens in the first trimester is incredibly important in terms of a child's subsequent development patterns of gene expression do seem to get stuck but again the difficulty is this is always at a population level we can't do it for individuals and i'm

i'm very skeptical about pat about explanations which are too clean and straightforward and based on one gene it in a blood sample um that may not be a good surrogate marker cortisol is a good surrogate marker for um for example stress levels but so often we do experiments really badly so for example people want to investigate what's happening in somebody's brain and they take a blood sample well why is that a good surrogate of what's happening in someone's brain it's pretty good for cortisol for stress but if you're trying to look for more um more

precise information it can be a very bad marker because the pattern of epigenetic modifications that you get in the right cells of the blood may bear no relationship to the pattern of epigenetic modifications that are actually present in the precise region of the brain involved in certain phenotypes so one has to be very careful not to expand the phrase epigenetics to mean anything a bit funky that we don't understand it must be epigenetics and so i'm i'm fairly skeptical about those data i'm not suggesting for a moment with work from those groups that they're doing

anything fraudulent not at all what i'm suggesting is i don't necessarily agree that the data is strong enough to support the conclusions that they draw right okay fair enough fair enough um the next question is from gita and she's asked how genetics and specific foods for example you mentioned sugar and alcohol are there any foods that cause a sharper change in epigenetics versus others no and it's again it's an impossible question 70 trillion cells all of them reacting to all sorts of stimuli coming in at the moment at any moment so which epigenetic modifications do

you look for remember i told you that say on the histones there are at least 60 different epigenetic modifications so even if you imagine one gene or even just one cluster of histone proteins at one gene there are 60 potential modifications in i don't know what would be the would it be one to the 60 sorry i wanted 60 60 to the whatever multifactorial combinations if you think of how 60 things can fit together then the problem is you can't with a person say the only stimulus happening to that person is that they are eating

turmeric at the moment and therefore any change that we see is due to the turmeric there will be a hundred other things happening in that person so you can't use foods to target a specific and drive a specific epigenetic change in humans as far as we are aware there is a real tendency to think if we could understand the epigenetic signatures we could identify super foods and everyone could have the superfoods and then we'd all be fine and it's not that much different from saying if only we could take a pill for everything nyla and

i got discussing this before the talk and i was saying i love epigenetics but it doesn't change the basic stuff which is that if you want a healthy lifestyle don't worry about if you want to be healthy superfoods etc don't worry about it just do the normal thing eat more fruit and veg cut down on our cold don't smoke stay a healthy weight do some exercise try and have strong relationships we are not going to find an epigenetic superfood that takes away those needs so it's this is about overall adaptations to one's environment it's very

difficult in humans to say one food that'll be fine that'll sort it all out we don't even know on the whole whether an epigenetic change is good bad or neutral and it might happen for half an hour and then disappear and have no long-term impact this is i cannot emphasize enough how dynamic and complex this system is so basically follow the health advice that's based on epidemiology and don't worry about what's happening to your epigenetic okay that's a great answer are you familiar with the concept of the environment of evolutionary adaptation or adaptedness and the

the potential like i read a book one time and the author was basically suggesting that we're living very far removed from this environment and if we can kind of align our lifestyle and behaviors more with those of our our ancestors where we spent loads of time like evolving as hunter gatherers etc and like making out adaptations like the paleo diet or the ketogenic diet or whatever that it would trigger more positive epigenetic responses um have you thought about that at all or is this complete nonsense from people um i thought about it i'm not a

huge fan i have to say um partly because well i'll give you an example i was chatting with a mate of mine who at that point was digging into the biggest stake i have ever seen um and he had nothing else there just this huge lump of a cow on his plate and um he said yes i'm following the paleo diet because that's how we should be and i looked at him and i said what do you suppose life expectancy was in the paleo times and he was he was like well probably about 25 30.

it was like okay yeah that's not necessarily great is it um and of course it was infectious diseases that tended to kill most people back then it wasn't necessarily um just because of the diet um also the paleo diet thing really irritates me because if you look at hunter-gatherer societies in the majority of cases meat makes up about 15 of the diet um it's actually a predominantly vegetable based diet and yet that always gets overlooked i think the most fantastic thing about humans which is also the most disastrous thing about humans is the fact we

are so divorced from our evolutionary antecedents um on the one hand we couldn't be having this conversation if we didn't constantly move away from what most other species do so we're fabulous on the other hand we're awful because we are having real problems with mental health epidemics we have real problems with what we do to the planet that's a whole different one don't get me on to that one um i don't think there is necessarily something we could define as being the natural human state and that we have fallen almost from this state of grace

um i mean i can't think of a bigger evolutionary avoidance strategy than vaccines and thank heavens for them yes so there's it's our ability to change our environment which is our greatest strength and our greatest weakness as a species and yes it is pretty clear that in certain areas such as what we've done to the way that we eat that is incredibly unhealthy for us if we do it the wrong way it is pretty clear i think that psychologically things like having no access to social support being in a highly urbanized environment those are bad

things for us whether that badness as it were is being mediated through the epigenetic system i don't know and i don't want to claim everything is epigenetics you know even the childhood trauma epigenetics is probably part of the answer but there will also be changes in the way that the brain connections are forming there's all sorts of stuff going on a hundred percent understand um our next question here is from uh monica are there any books websites or articles you'd highly recommend in in this subject well i do so i think the epigenetics revolution is

a cracking book myself you know so if i'm still repeating on that one um be a bit careful there are some books which are just shockingly awful they're just you know epigenetics is the answer to everything and it isn't um some of the websites there was a i would have to check if it's still operational but there's a very good one called epigenesis which is e-p-i-g-e-n-e-s-y-s and that was the public engagement website of a pan-european consortium working on epigenetics and that one was fantastic you could spend days happily going through that website because they were

really passionate about communicating the science but also communicating where there's stuff we don't know and things we haven't found out about um and i don't want to sound snobbish but i would absolutely on youtube just check out the affiliations of people who are giving the talks etc um you know there are fabulous people working in epigenetics so focus on them you know focus on the ones who really seem like they have the academic credibility there's beautiful work going on in this field okay cool um we'll link to these in you're going to get email the

resources document after everybody and we'll link to these or any any links mentioned um in the talk there um so we've got one from anna are there any examples of a single base change or other genetic mutations in a gene that can cause epigenetic changes yeah absolutely so the rett syndrome one is a classic one in that the children can no longer read epigenetic changes but um the other ones are um we find in certain cancers so there are certain types of cancer where what has happened is the patient's dna has mutated so there's been

a mutation and that mutation means that an epigenetic protein starts doing the wrong job and that creates a cascade so it switches certain genes on much much more highly than they should be switched on and that starts driving the cell towards cancer so we definitely have examples where you're either born with a mutation that messes up the genetic system or you randomly acquire a mutation that messes it up so you can have a genetic mutation where the final disease is mediated through epigenetic mechanisms and actually when that happens what you try to do is create

a drug to change the epigenetic process that's going wrong rather than trying to reverse the genetic mutation because that's much much harder okay great um we've just got time for one more question it's from ileana um what are your thoughts on the work of bruce lipton okay so some of you may want to check out bruce lipton what i would say is that i come at epigenetics and at human psychology in a very from a very different angle from bruce lipton he and i i think have very different cognitive frameworks on this one so yeah

it's it it's not my thing would be what i would say okay fair enough um well so that's all i've got time for i just want to say thank you so much for a brilliant presentation i think everyone has loved this and yeah everybody um thanks for tuning in we'll be back now at one o'clock with our second talk from uh martin de lea so nasa thanks a million and hope you enjoy the rest of your your sunday pleasure and i hope you guys all enjoy the rest of the day it looks like it's gonna

be an awesome day thank you so much for inviting me awesome okay see you guys soon