Dr. Isabelle Mansuy

In this episode of Just Like Nana, host Amie (Elizabeth) Penny Sayler sits down with Dr. Isabelle Mansuy, a Professor in Neuroepigenetics. They get to the root of ancestral trauma, starting with the groundbreaking science of epigenetics and the transgenerational effects of trauma. 

About Dr. Isabelle Mansuy

Dr. Isabelle Mansuy is a leading expert in the field of neuroepigenetics and a professor based in Switzerland. Her pioneering research focuses on the biological mechanisms of how traumatic life experiences, particularly those occurring in early childhood, modify mental and physical health across generations. Through her extensive work with mouse models, Dr. Mansuy has provided some of the most compelling evidence to date that traumatic signals can be carried in the germline (sperm cells), affecting the behavior and physiology of offspring up to five generations later. 

In This Episode, You’ll Learn:

• While your DNA sequence (the hardware) is fixed, your epigenome (the software) is dynamic and can be modulated by both your life experiences and the life experiences of your ancestors.
• Early-life trauma creates epigenetic signals in sperm (germ) cells, which transmit the consequences of that trauma to future generations. 

Connect with Dr. Isabelle Mansuy

Website: https://www.mansuylab.ch/team/isabellemansuy 

Connect with the Show

Are you curious about the "Elizabeths" in your own family tree? We want to hear from you!

• Website: justlikenana.com
• Share Your Story: If you have a family story or trauma you’re exploring, reach out via our website for a chance to be interviewed.

Connect with Just Like Nana's Website.

A proud member of the Feminist Podcasters Collective.

Theme music by Carter Penny.

Transcript

Amie Penny Sayler: 0:22

We're so excited to have you here with us at Just Like Nana today, I am absolutely thrilled to be interviewing Dr. Isabelle Mansuy. She runs a neuroepigenics lab as part of the Brain Research Institute at the University Zurich and the Institute for Neuroscience at the Swiss Federal Institute of Technology. She studies generational trauma. Dr. Mansuy's credentials and accolades are too numerous to list highlights. She's a member of the Swiss Academy of Medical Science and was elected Knight of the Legion of Honor in France. Welcome, yeah, thank you. Lovely to meet you. Thank you so much for being here. My pleasure. As you know, this is a podcast that talks all things, we call it ancestral trauma, but intergenerational trauma, generational trauma, I would love to start like we do with every guest, and just hear one of your favorite memories of a grandma or Nana, and what you call her, would love to hear that.

Dr. Isabelle Mansuy: 1:28

I'm afraid I don't have any special memory with my grandmas, because both were somewhat one was very authoritarian, authoritarian. Ah, and the other one was sweet, but for a reason, yeah, I looked for for memory, but I don't have any anything special.

Amie Penny Sayler: 1:54

That's okay. What's your word for grandma?

Dr. Isabelle Mansuy: 1:57

For it depends. One of them was grammar, which is very formal. Because in that family from my mother's side, my mother herself was not saying to, you know, in French, you we say tu or vous, this very, very formal way to approach, to name someone, they were very formal, even if they were from the from the countryside. The other grandma, we called her meme, meme, which means he's really not that sweet because memory is very old. Means very old lady. Meme.

Amie Penny Sayler: 2:43

I would love to talk about your work. This is a very kind of simplistic question, but, you know, we call this ancestral trauma. It's also referred to as intergenerational trauma, or generational trauma. I kind of think of intergenerational trauma as more trauma that follows through a family line, and we'll talk about your work in epigenetics, generational trauma as more kind of a generation of people, so how war, historical events affect that generation, and then ancestral trauma is a little bit more of a human kind of woo and that scientific way to talk about your family and how your family affects who you are. Do you see a difference in those terms? What term do you use?

Dr. Isabelle Mansuy: 3:28

We don't use the term transgenerational ones ancestral trauma, because it's not precise enough, and it's indeed misleading and wrong, because it's not the trauma which is transgenerational, it's consequences, and it's very important, because if you have a transgenerational or intergenerational trauma, it means that the trauma itself is reiterated, reproduced at each generation, right? And this is not the case. Indeed. What people generally mean is that there was trauma in one of the prior generations, in the ancestors, and that the descendants are subjected to the consequences, to the effects, generally and negative effects of that trauma. So I think it's very important to be to be more precise and say that I know that it's a shortcut, which may be convenient, but because people understand it somewhat, but it can be very misleading, because if let's say you take someone, or let's say a man, a man who has been traumatized, abused or whatever, when he was a young boy, he himself will be violent with his children and recapitulate, repeat the conditions that made him violent, depressed and anti social and everything, and then the following generation will again be exposed to exactly the same trauma. So then it's very different from the inheritance. Where it's really the consequences, because from a biological perspective, we are talking about different things.

Amie Penny Sayler: 5:06

Yeah, okay, that's a great point. And that kind of leads into, can you explain epigenetics? What does it mean? How does it inform your work?

Dr. Isabelle Mansuy: 5:15

Yeah, epigenetics is the complement of genetics. So in each single cell in our body, we have the genome, which is the DNA sequence. It's a little bit like the hardware of your computer. And in these cells, on top of the DNA sequence, next to the DNA sequence, there are epigenetic factors, which can be very different. So why there is one code, just one code made four different bases, of course, the code is super long and complex, but it's just one code for the epigenome. There are many different epigenetic marks which interact, which are very different from cell to cell. And these epigenetic marks which are on the DNA itself and on the DNA. They modulate the activity of the genome. So it's a little bit like the softwares of the computer. A computer without softwares has the code, but it's useless. You cannot do anything. You need the software's to read it, interpret it, and so on. And you need multiple softwares. And these softwares, you can add them, remove them, they can interact, and so on. And that's, you know, the also, the that gives the right notion of the level of complexity. While there is one code, the epigenome is extremely complex. One code, and if you damage it, you break you break it. If your hard drive has a scratch. It's done, right? You cannot fix it. The DNA is big, like that. If you have mutations due to X rays, carcinogens, UVs, they cannot be really fixed. While the epigenome, it's very dynamic. It can be modulated, it can be changed, it can be corrected, repaired. So it's a complement of the genome. It's necessary to its function. But it has another scale, another level, another dimension, in its dynamics and reversibility, in a way, and the environmental factors, what we experience, what we eat, the sport we have, our emotions, everything, everything outside, modulates the epigenome in every single cell of our body, and maybe differently in different cells. If you eat good food, vegetable and fruits, they will act on all your cells, but differently on your brain cells and on your liver cells. If you go for a run, the epigenome will be changed in your body, but differently in muscle cells and in skin cells. So genome, it's another properties. It's different from one cell to the next, while the genome is exactly the same in every single celling of our body, okay?

Amie Penny Sayler: 8:02

And the activation or modulation of the what word did you use -- the epigenome?

Dr. Isabelle Mansuy: 8:09

The genome is the DNA code, right? The Genome genes, they are gene, okay, yes. And sequences outside genes, genes. It's only a very small proportion of the long sequence, right? But all the races sequences in between genes. So the epigenome, epigenetic factors, they modulate activity of the genome, okay?

Amie Penny Sayler: 8:29

And then it will occur, you know, getting back to your example of fruits and vegetables and running, it's modulating at the time, but then that also continues to have effects afterward. Is that fair?

Dr. Isabelle Mansuy: 8:40

Of course, it modulates, you know, the DNA is active all the time. Of course, genes are not expressed all the time, but the DNA itself, there is always something going on around activity around the DNA. And epigenetic factors are the same. They are very dynamic, and the effect can be immediate. But some of the effects, some of these changes in epigenetic factors, they can last, and some of these changes, they can be permanent.

Amie Penny Sayler: 9:17

Maybe this is a good time, because I have more questions about humans. But can you explain your work?

Dr. Isabelle Mansuy: 9:23

My work is to study or try to understand what mechanisms operate in the body, which can explain how life experiences, in particular in childhood, can modify our mental and physical health. So we are particularly interested in these factors in germ cells, because we want to understand how life experiences can modify people across generations. And here, when we are talking about across generations, we really focus. On germline dependent transmission, because what is the link between a father and his children? Biology? Okay, biologically, what is the link? It's the sperm, right? Sperm provides the genome, the genetic luggage and the epigenetic luggage of the Father to the child. And we are interested in this, in the mechanism at this level. So the biological baggage, luggage signals that a father can pass to the children, and which carry information about his own life experiences.

Amie Penny Sayler: 10:38

And that's interesting, because I'm curious about the difference between men and women. So obviously, women are born with their ova, what they're going to pass on to their children, use to make their children, and men are consistently reproducing sperm. So is there a difference, like, are the life experiences of a woman even further embedded? If that makes any sort of sense.

Dr. Isabelle Mansuy: 11:01

We don't know, but probably not, because, you know, sperm, they don't come, of course, they are produced all the time, but they come from a progenitor cell. And this progenitor cell is present in the in the man, in the boy, very early on. So if this progenitor cell is affected by stress, by poor diet, or endocrine disruptors, or whatever. It's possible that some of the alterations will stay this progenitor cells, which is going to be produced in the future. We'll have that, of course. Now if we talk, we take an adult man who gets drunk one evening, lots of alcohol in blood, lots of alcohol and metabolize in the testis and probably germ cells, including sperm cells, may be affected at the time, but then once spermatogenesis, you know, continues to produce the cells which were present in testis and sperm cells, sperm cells and all the prior stages present in his body at that time may be exposed, but once they have all been cleared and the effects should not be there anymore, unless the progenitor cells themselves have been affected, but the progenitor cells, they are protected in testis. There is a blood testis barrier which protects these germ cells. So high level of alcohol for just a couple of hours is not going to be enough. I don't know. I don't know enough to affect germ cells, the progenitor cells, we don't really know, actually, no one has really looked at that in in human, because in human you cannot collect, you cannot call I mean, we do that in mice, but we need to sacrifice the mice to collect these cells in human, you know, pronito cells. They are called spermatogonia, stem cells. They are intestines. They are embedded in testes. I mean, you would need to extract the testes to look at them.

Amie Penny Sayler: 13:02

Okay, can't do that. So can you describe your work with the mice?

Dr. Isabelle Mansuy: 13:08

So we focus on early life experiences, so postnatal after birth, during the first couple of weeks of birth, and we are interested in the effect of traumatic experiences during that time. So it's a critical time window for human and mice, because, you know, the body is in development, and many of the cellular barriers I mentioned the blood test is barrier, but there is also a blood brain barrier. Many of these barriers, of the tissues are not completely formed, and since things are still undergoing development. So for some aspects, it's a critical window of susceptibility. So we expose mouse pups, just newborns, to stress, and it's a chronic stress. It's unpredictable maternal separation combined with unpredictable maternal stress each day at any time during the day for two weeks, so 14 days. And this is a lot, it's chronic, because a mouse perp is wind. So is it can be doesn't need the mother anymore after three weeks. So it's 2/3 of the early childhood, if she wants, right? This would correspond in humans to from age zero to age I would say 11. Well, maybe Okay, and it's a chronic stress. It's everyday. And then we these pups after they have been stressed. They are one week after the stress. Are one week with a mother, with no disturbances, no stress, no nothing. So a quiet week, in a way. And then so there are wind. And then we wait until they are adult. So they are males and females, of course, in meters. And we test the behavior, the physiology, the metabolism. We do many, many analysis, and we found that they are depressed. They. Have increased risk taking. They are anti social. They have problems of memory. They have problems cardiovascular problems, immune immunological problems, so many, many things are altered in these animals, and we see that through the fathers, when these males, which were themselves exposed to the stress when they pups, when they were young. If they get an offspring, the offspring will have very comparable phenotypes, symptoms. And if we take this offspring, breathe it again, I get a grand offspring again, we see symptoms. And we did this to the fifth generation, and still in the fifth Wow. There are some symptoms, not all of them, but risk taking is one of the symptoms, which is still observed in the fifth generation. Now emails the little females. So the Sisters of the of these males that we bred to the fifth generation. We bred them once. So we went to the second generation. We did not go further, and we saw also that the second generation has symptoms similar to the females which were directly exposed themselves. So all of these indicates that there is indeed perpetuation of the effect of trauma, at least in the battery line. We can firmly say this in the battery line, the mature line, we don't know, because we did not go further enough, because you realize a mouse pub, like a boy, is exposed to trauma or whatever, his cells, including his future sperm cells, are affected, are directly exposed in a way. So it's not too surprising that his children may have effects, right? So if now we want really to talk about transgenerational transmission, we need to go one generation further, the generation when not a single cell, not even the germ cell, that gave rise to this individual, the sperm cell that gave rise to this individual has never been exposed at any point in time to exposure. And in females, it's the same. You imagine an expecting mother. So the mother her baby, the germ cells in the baby are affected, so which means her child and the child of her child, so three generations in one lady are exposed. And indeed, in the US, there is a really high surge of autism, autistic spectrum disorder, and many people think that it's linked to to endocrine disruptors, in particular, cocktails of drugs which were given to women to avoid miscarriage that was very prominent in the US, because these drugs, I mean, you know, Americans have been eating medications a lot more than Europeans Since a long time, longer than here and now you see many more cases of autism in the grandchildren of these ladies in the 60s, 50s, 60s, 70s, who had been taken, taking these, these medications. So it's one example.

Amie Penny Sayler: 18:18

Is anyone directly studying that?

Dr. Isabelle Mansuy: 18:21

Well, there is a lady from California, Jill Escher. Have you heard of Jill Escher? She's a lawyer by training, but herself, she's born in 65 and her mother took some of these medications, and she was very struck. She's a very, very smart lady. She has three children. The three are autistic. Two very severely. One is okay, manages his life on his own. So she she really educated her time her life to dig into this. And she has collected lots of information about families in the US who have been exposed to mothers who have been exposed to that medication, but also to anesthetics. She has expanded. She's not a biologist, she's not a researchers, but she has been really outstanding in collecting data. It's epidemiological data. So now, of course, there are studies which are done in humans, and in humans, it's only correlative. You cannot prove that's really the cause of the symptoms in the children or grandchildren in mice. We can, because we can exclude many confounding factors in terms of a trauma, this been done. I mean, our work really shows that it is in the germ line, endocrine disruptors. There is a very strong proof as well, high fat diet, low protein diet, the same. Now, of course, we would need to demonstrate the causality in humans. This will not be possible at all because of confounding factors, again, but it's that the status of the research at the moment is really suggesting really strongly that this. Suitcase in humans as well.

Amie Penny Sayler: 20:03

So just to say that a little bit differently, and to state the obvious, the differences in the mouse pups, you can control for all the other factors. So you know that it's directly the trauma that's causing the consequences, you know, for future generations. But in humans, obviously there's too much going on. You live an entire life. You're affected by what's going on around you. And of course, we can't put a child in a lab and not have them, you know, experience any of the rest of life. So that's sort of what you're describing exactly.

Dr. Isabelle Mansuy: 20:29

There was this, the fact that we control everything, and that's these animals. It's the only experience they have. They don't have any other experience. Not only we control, but it's the only experience. Everything remains the same. And also, because we can use strategies, for instance, these pups which have been so the progeny of individuals of mice which have been exposed to stress, we can take the pups and give them to a normal mother, a mother which has not normal, to a naive mother, a mother which has not been traumatized itself. To really check whether maternal care may be playing a role here, and this is even if they are raised by non traumatized mother, we still see the phenotypes we have done IVF, so we take the sperm of traumatized maze and we produce an offspring without meeting, without breeding, just by using the sperm. Even if we take only the inside of sperm cells, the RNA, and we inject it into an embryo, once an embryo just control and we see phenotypes in the offspring. So we've used multiple strategies to really prove that it's in the sperm sperm cells that there are signals of a trauma, which can be passed through the offspring and responsible for symptoms.

Amie Penny Sayler: 21:53

Wow, that's fascinating, and obviously in humans, as you pointed out, you sometimes with mouse pups, we'll give them to what you call the naive mother who hasn't experienced the trauma. Often, in humans, the families continue to experience the consequences of the trauma, or even new events that start to affect that.

Dr. Isabelle Mansuy: 22:15

Because if you take intra familial violence, you know, violence in families. I mean, usually it's associated with many different things, physical violence, verbal violence, alcohol abuse, I mean, neglect, humiliation, these kind of things.

Amie Penny Sayler: 22:44

I was going to ask you about the healing or the lessening of the consequences of the original trauma. And it sounds like, from what you're describing, that the consequences or symptoms or sort of, you know, behavior lessens through the generations, but it can go through five generations. But is that accurate, or is it still I guess, do you notice a a healing? I'm using that word very loosely, of the trauma through the generation, or the consequences of the trauma through the generations.

Dr. Isabelle Mansuy: 23:17

There are symptoms which disappear in a way. But you know, it all depends on the strength of the trauma. And unlike in humans, in our case, there is, there are only two weeks of trauma, only two weeks. So if it's a generation, you know, the ancestors were born two years before, even three, four years before. So there are no other repeating, no other possibility of or event which could revive the trauma, unlike in humans. So if we would use an even stronger trauma, have it, longer have it, you know, adding different things, perhaps it would still affect individuals in the sixth or seventh generation. We don't know, so we cannot really make a firm statement about that.

Amie Penny Sayler: 24:22

I'm curious about kind of emerging technologies that are advancing your work, and maybe you want to talk about this a little bit you do the Biannual International Epigenetic Inheritance Symposium. Is that correct? Indeed, yeah, what sort of came out of that really intrigued you, excited you.

Dr. Isabelle Mansuy: 24:43

Well, the fact that there are more and more observations which confirm that exposure to whatever diet, dietary insult, trauma, anesthetics, arsenic, many different exposures, they do have. Of effects across generations, and the refinement of the phenotyping, so the refinement of the of the effects, and also more and more knowledge on the molecular correlate of that. What does it mean, for instance, to have a diabetic state in a mouse, descendants of a male which has been treated with hyper diet. What are the molecular alterations? And try to link the molecular alteration, they say, liver, with those observed sperm, because there is a phenotype and there is the what causes the phenotype? And if indeed we suppose that, we assume that is the sperm which has the signals infused with the oocyte, it gives an embryo which develops and develops, what is the link between these signals in sperm? And let's say liver dysfunctions or memory problems in your in adulthood. How does this unfold and gives rise to these symptoms? It's very difficult to understand that and to dissect out all the different steps, so there is more and more knowledge about what may happen. Another thing is that for paradigms which are not necessarily very strong. I mean, ours is super strong. So each time we see the phenotypes in the offspring, Grant offspring as well. There are many paradigms which are mild and there there is lots of viability in the effect, which does not mean that they should not be studied, because they may indeed be more, maybe closer to what's happening in humans. It's a little bit of this, a little bit of that, and that it accumulates. And that in some people, it will show that in others it will not show. So people are now starting to exploit or try to extract information using novel statistical models to understand, yeah, to really model and have a conceptual framework to understand the different possibilities. What are the nuances that an exposure could bring in terms of symptoms, phenotypes, effects across generations?

Amie Penny Sayler: 27:20

I want to ask you about the term phenotypes. What exactly do you mean when you say that?

Dr. Isabelle Mansuy: 27:24

A phenotype is a trait, let's say a behavioral phenotype, a metabolic phenotype, physiological phenotype, it's a function, it's a trait. I mean, you have brown hair, it's a phenotype. You have a hypertension, or you or someone has hyper pressure, it's really a feature, okay? And in mice, it's something that we can quantify and define qualitatively, very precisely. You.

Amie Penny Sayler: 28:04

Where can people follow your work? See what you're doing, support what you're doing, look at your publications. Where should they go?

Dr. Isabelle Mansuy: 28:12

Oh, we have a website, okay, which is, I think, 3w month lab. I think if you Google my name.

Amie Penny Sayler: 28:22

Yeah, and we will link it too, yeah.

Dr. Isabelle Mansuy: 28:25

Oh, great for support. I don't know that would be great, because it's, it's a really hard field of research which still hits quite some resistance, because, you know, the very classical view on heredity is that genetic, you are your genes, right? Something different. We say that you are not only your genes, but you are what you experience, and you also what your parents experience, and maybe what your grandparents experience, which is a completely different framework, conceptual framework for heredity and geneticists who resist, who don't, don't want to hear that, even if there is very strong evidence, because, you know, it's it's like a dogma that heredity is genetic. It's a dogma. And even among the most intellectuals, you know, big professors, yes, some of them are not prepared to reconsider that. So it's a field of research which is really, really hard. It's hard to publish. It has to raise funding for research. Everything is hard, much harder than, you know, people who use big microscopes and look into the brain and just report what they see, right? There is no concept, there is no hypothesis, there is no risk in what they do. Because, you know, you just take something, observe and report, and that's it. So with all the financial restrictions which are ongoing, not just in us, but also in Switzerland, even if Switzerland is super privileged for that, and if you know funding, public funding agencies. They are have limited funds. Of course, they will choose to fund research that is pedestrian, that is secure, that does not raise any question, or that is is guaranteed in terms of results. So we suffer a lot from from that, unfortunately. But I think it's, it's so important and so relevant for human beings. It's very important that people are aware of that.

Amie Penny Sayler: 30:24

My last question is, what do you hope that your work kind of gives us?

Dr. Isabelle Mansuy: 30:30

Yeah, that people understand, understand the biology a bit better and understand, yeah, heredity and for for for diseases like depression. You know, depression, there is a lot of taboo. Many people are depressed. They don't want to admit that they are depressed, because, in our society, being depressed means you fail your life, right? You are weak. You cannot resist. You are too weak. Yeah, a lot of guilt. That's why, one of the reasons why many depressed people don't consult, because they don't want to admit for themselves, and they don't want to you know, there are rarely any coming out about depression. Now, if you consider that indeed, that may they may be nothing wrong with yourself, with your life, with your choice in life, and but that may come from your parents or even your grandparents, yeah, just you inherited this shape of nose. There is nothing who is just genetics. But that it also may also be the case for every other function in your in your brain, including dysfunction in the brain, like depression, schizophrenia, so that can really help a lot people understand where the condition may come from, and consult and maybe that may be easier to fix. Because if now you consider that depression is just like any other disease, just have to analyze it. See what are the symptoms? See what you can do to alleviate the symptoms and life goes on. Instead of saying, I feel guilty, I will never get out of that and so on. I mean, colleagues, psychiatrists say that that can make a very big difference, actually. Wow. Cardiovascular Disease is the same because, I mean, we found, for instance, in our mouse model, that they have heart failure. You see what that stress? I mean, they have not eaten anything bad, they don't smoke, they don't you know, they have normal activity. So what is the what is the link? How come it was not known that, indeed, cardiovascular alterations in an animal could be due to the stress of the grandfather. So if audiologists know that you see, it can also change completely the attitude towards medicine and maybe towards diagnostics and understand the cause of disease, because rather than treating just the consequences of disease, if you understand the cause, then that can really change approaches to medicine.

Amie Penny Sayler: 33:08

That's wonderful. Well, thank you so much for what you do and then for talking with us today. So appreciative, doctor.

Dr. Isabelle Mansuy: 33:16

Thank you. Thanks for your interest.