Tag Archives: Epigenetics

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A spur to prick the sides of my intent

Suppose it were possible to change things about your own birth? What a great idea, right? Just think what that might mean: at the very least, perhaps, that you would not be imprisoned by whatever genetics you were allotted; you might actually have a chance to be the master of your own fate; and if you chose, be able to excel in fields currently beyond your reach.

And yet, would it even matter if it were yours to choose? Surely, not every daughter born to university professors succeeds as well as her parents; not every wealthy scion is able to make use of the educational opportunities he is able to access. It seems to me that there is more to it than the circumstances of birth -or the ticket you were issued in the chromosomal lottery: even hereditary instructions are malleable.

Genes are only blueprints -guidelines in a way- and what gets built in the end, often depends on how consistently each instruction is followed. Sometimes, circumstances prevent, or simply delay, completion of the initial plan. One of the mechanisms that allows this is epigenetic interference with the chromosomal directions: chemical signals that turn genes on or off -changes that are not inherited through DNA but rather result from interactions between genetic processes and experience. And these signals, or switches if you will, can be activated by a variety of circumstances: environment, stress, illness, diet, and even intrauterine factors- just to name a few. Genes are not the handcuffs we once thought they were.

But, I think most of us suspected that the exigencies imposed by birth were not absolute long before we knew anything about epigenetics. Or genes… or inheritance, for that matter. Philosophy has long wondered about who, what, and why we are; I was reminded of this by an essay written by Ada Jaarsma, a professor of philosophy at Mount Royal University in Calgary. https://aeon.co/essays/in-genetics-as-in-philosophy-existence-precedes-essence?

She writes that ‘In the early aftermath of the war, the French philosophers Simone de Beauvoir and Jean-Paul Sartre used the term ‘existential’ to mark a radically first-person approach to history. Instead of the seemingly implacable nature of an event in time, these existentialists pointed to the subjective meaning that such events hold.’ Indeed, ‘I need to choose the circumstances of my birth, Sartre explained in Being and Nothingness (1943).’

On its own, his statement seems more metaphor than prescriptive, and yet, reality is conditional, isn’t it? To some extent, we all control how we perceive it, and therefore what it is like for each of us. I, like many of those in my philosophy lectures, was attracted to existentialism, and yet, although the poster figures were people like Sartre and Camus, I was drawn to Simone de Beauvoir, Sartre’s long-time friend. I loved her metaphor of existence being a drama.

And yet, one of their rallying cries was ‘existence precedes essence’ which I never understood. The only thing I could figure was that they were simply saying that you couldn’t become anything unless you existed -and that didn’t seem particularly profound to me at the time. But Jaarsma helped me with this when she explained that ‘Beauvoir and Sartre were drawing attention to the utterly singular way in which we each become the selves that we are, with our own memories, stories and storytelling habits.’ There is for each of us, some control, if and when we weave these into some form of meaning. It’s the process of weaving that marks our humanity: that takes us from being a ‘thing’ into a ‘project’, to paraphrase Beauvoir from her Pyrrhus and Cineas. To choose our own births, in other words.

Jaarsma’s essay deals with far more than my brief précis has included, but I suppose we only take what information we need from any text. For me, it was the memory of those introductory philosophy lectures in my early years at university -my impressionable years, perhaps, but maybe also my formative years.

I loved philosophy and thought long and hard about it for those all-night discussions that my three close friends and I seemed fated for every Saturday night over a few beers. One of them, Arvid, was a Science major, and another, Bertram, was in Engineering, and then there was Judy who was enrolled in Arts, but intended to switch to philosophy when she had enough credits, or whatever. The discussions were really arguments, but isn’t that what philosophy is all about?

At any rate, the time that sticks out in my memory, was when Judy and I had just been to a seminar on Simone de Beauvoir earlier that week and were both primed with her feminist perspective.  Feminism was still considered quite radical at the time- and although I didn’t understand most of it, she decided to spring it on the other two.

“That’s just crap,” was Arvid’s traditional response to feminism -most of us were still trapped in the Zeitgeist of the time, I’m afraid. Even Bertie, who professed to a neutrality he couldn’t maintain for more than two or three sentences in an argument, wasn’t able to see why we men should have to yield anything to ‘the other side’ as he put it.

“We are the stories we tell,” I tried to interject to calm him down.

“Well, I was brought up with a different story, G,” he said with clenched jaws as he tried to stare me down.

Judy was sitting on the floor, her head leaning against the wall in the little dorm room where we had gathered, and had a sip of her beer. “And what was that story, Bertie?”

His expression softened as he tried to put it into words. “Well…” -Bertie hated confrontation- “I guess that I don’t see the need to capitulate…”

“Is that what it would be if you accepted women as equals, Bertie: capitulation…?”

He looked confused. “But I do accept women as equals.” Judy wrinkled her nose at that and he blushed. “I mean, we should all do what we’re good at, right…?”

“And what are women good at?” She pinned him to the wall he was leaning against with her eyes. “Having babies? Cooking? Cleaning the house?” She blinked seductively. “Being a good wife for her man?”

“Well, no…”

“A woman philosopher named Simone de Beauvoir once said ‘I am not a thing, but a project’. What do you think she meant, Bertie,” she said with a glance in my direction.

Bertie seemed flustered at the question. “Uhmm, that she was still working at what she was good at? Or…” He hesitated; he had obviously not thought about women like this before.

“Or that she could become somebody else?” Judy interjected, smiling at his discomfort. “Maybe whatever she wanted…? Perhaps her project was to tell a story –her story?”

“But…” Bertie had a quick swallow of his beer, and stared at her. “Just because you tell a story about yourself doesn’t make it true, or anything.” He thought about it for a moment. “I mean, maybe you’re just making it up -telling yourself something that will never happen…”

“It’s a goal though, isn’t it Bertie? Something to aim for.”

He shook his head. “But suppose it’s unrealistic…”

She sighed and smiled at him -sadly, I thought- then put down her beer. “What’s your story?”

He closed his eyes, as if he wished he’d never said anything. “I… I don’t really have one, I don’t think.”

Judy smiled again, this time like a mother, or maybe a sister. “Yes you do, Bertie,” she said softly. “You want to be an Engineer.”

He slowly shook his head, eyes still closed as if she’d hit a sore point. “I told myself I did, but now I’m not so sure.” He opened his eyes slowly and let his eyes rest gently on her cheek. “I don’t think I can do it, you know…”

Judy got up off the floor and went over to sit beside him. “Sometimes you just have to believe the story you wrote, Bertie.” She touched his shoulder affectionately. “At this stage in our lives, the story is all we have…”

I don’t remember much of the night after that, but I did happen to run into Bertie years later. “So, what are you doing with yourself nowadays, G?” he said after we shook hands and did the man-thing of slapping each other’s shoulder. “You always wanted to be a doctor, I remember…”

I nodded my head. “And you were going to be an engineer, weren’t you…?” I was curious about what had happened to him. Circumstances change as semesters bring new classes, and our little group of friends gradually dissolved. Within a year, we’d pretty well lost touch with each other…

“Flunked out after a couple of years,” he answered. “Anyway, I switched into science like -what was his name? Arvid? Now I’m a teacher.”

He looked happy enough, but as I was leaving, I saw the wistful expression on his face. I think I must have stirred some long-buried memories; I think he remembered he’d had a different story once…

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The Mom and Pop Team

From time to time, I think we all need reassurance that we matter. That our seat at the game has not been taken by someone else. Could not be taken… Maybe that’s why we’re given names -so there’s no mistake. And if we’re not there all the time, it’s only because we sometimes have other duties to perform.

In many species, the male role in procreation can seem like that, I suppose: a postal service that’s only charged with delivering letters, not reading them, not dealing with the contents. At least that’s how it looks from across the street. On closer inspection, though, it would seem that the delivered mail is far more complex than it first appeared. It’s almost as if whoever reads the letter not only sees the blueprint, and the construction manual, but much like reading a newspaper, also learns of other important things which, at first glance seemed unrelated, but in the end, profoundly affect the building.

These processes would obviously be difficult to study in humans, so often we have to model them in other species and extrapolate the results to our own kind. Two articles in the Smithsonian magazine outline some of this information.

There are at least two time frames when the male influence on the resulting offspring was unsuspected: before conception -in fact, even before meeting his potential mate- and during growth and development of the fetus, and even its neonatal care. The how is interesting, but equally so is the why, I think.

First, let’s consider the production of sperm in isolation from its immediate need. https://www.smithsonianmag.com/science-nature/dads-pass-more-genetics-their-sperm-180969760

Sperm are produced in the testes, and then travel to a storage area via the epididymis -a long, wriggly 6 meter long tube in the human. It’s in the epididymis that the sperm mature and become motile. ‘As sperm traverse the male reproductive system, they jettison and acquire non-genetic cargo that fundamentally alters sperm before ejaculation. These modifications not only communicate the father’s current state of wellbeing, but can also have drastic consequences on the viability of future offspring.’ Sperm contain genes, of course, but simply having the instructions doesn’t mean they will be carried out. Genes can be turned on, off, or down, by other mechanisms –epigenetics. ‘One of the most powerful members of the epigenetic toolkit is a class of molecules called small RNAs. Small RNAs can conceal genetic information from the cellular machinery that carries out their instructions, effectively ghosting genes out of existence.’ The father’s previous diet, stress levels, and so forth can all have an effect on these small RNAs, and the small RNAs are in turn shed or reacquired as the sperm continue their journeys along the epididymis.

And then, as I mentioned, there is an effect on the developing embryo whether or not the male is actively involved with the female during her gestation or in the subsequent rearing of their offspring. https://www.smithsonianmag.com/science-nature/how-dads-genes-can-prepare-mom-parenthood-180969793  Although the data is from mice, it turns out that ‘The paternal genes a fetus carries can impact the maternal brain during pregnancy, priming her to allocate more or less of her time to tending to her kids.’

‘A child that procures as many nutrients as possible from mom can secure a father’s lineage at no cost to him—but a mother still needs to prioritize her own wellbeing during pregnancy and early childcare.

‘This sexual conflict is well exemplified by a gene called Igf2, which drives the rapid growth of fetal cells. Like most of our genetic material, Igf2 is inherited in pairs—one copy from mom and one copy from dad. But in contrast to other genes, only the version from dad gets put to work. The Igf2 from mom, on the other hand, is stifled through a chemical modification that acts like a muffler on an engine. Mom’s Igf2 DNA undergoes no changes—but the gene’s instructions can no longer be heard over the din of the cellular milieu. […] If an error occurs that also switches on the mother’s copy of Igf2, the baby quickly balloons in size. This could be good news for dad—a big baby is more likely to survive—but mom can get in serious trouble if she has to carry and birth an unmanageably large fetus.

‘To guard against this possibility, females have developed their own failsafe: another gene called Igf2r. The “r” stands for “receptor”: the product of this gene can sop up free-floating IGF-2 proteins before they exert their growth-promoting effects. Unsurprisingly, dad’s copy of Igf2r stays quiet. Such is the phenomenon of genomic imprinting—a form of non-genetic inheritance in which both copies of a gene exist, but only one parent’s version is left intact. Over 150 imprinted genes have been confirmed in mice, about half of which have conserved counterparts in humans.’

Suffice it to say that there are several other paternal genes that code for growth or neonatal behaviours that can affect the mother’s response and subsequent care of her offspring -a kind of effect that evolution has decided would be in the best interests of all concerned.

For example, ‘expression of an imprinted gene called Phlda2 in a fetus hinders the growth of hormone-secreting placental cells. These hormones recruit nutrients to support early development. Unsurprisingly, the offspring’s paternal copy of Phlda2 is kept under wraps. But mothers want their copy to remain switched on. […] Other researchers had noted that these hormones weren’t just working in the placenta, however. Throughout pregnancy, they were actually spreading throughout the mother’s body and accumulating in her brain—leading John [professor of biology at Cardiff University] to suspect that they could also be encouraging a mother to care for her young. […] The team’s work lends credence to the idea that fathers don’t dictate the health of children through genetic inheritance alone. In cases like these, they can even utilize the fetus as a chemical envoy in this battle between male and female, swaying a mother’s priorities towards more attentive childcare.’

During many of the years when I was in active practice of obstetrics, I often felt I needed to be an apologist for the father who did not have to suffer the many exigencies of pregnancy, not to mention the difficulties of labour and delivery. Clearly, after fertilization, his role in the process seemed merely supportive, and often peripheral.

Were I to start my career over again, though, perhaps I could put in a louder word for the importance of our male side -although I’m not at all sure mom would be listening as intently at the end.

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Food for Thought

There’s something encouraging about the fact that we are not simply our genes. We’ve moved on -evolved, I guess. They are still the recipes, the instructions, but as every chef knows, you don’t always have to include all of the ingredients to get a good result. Genes are perhaps more akin to a first draft for a project. Suggestions. Options. They are, in effect, travel guides -road maps- that tell you what you could do and how you might go about doing it, but although the tickets are bought, you don’t have to get on the bus. Who we are –what we are- is not as pre-ordained as we previously thought. Just because there is a light switch on the wall, doesn’t mean it has to be turned on unless it’s needed. There is a mechanism, as Wikipedia puts it, for ‘cellular and physiological phenotypic trait variations that are caused by external or environmental factors that switch genes on and off and affect how cells read genes instead of being caused by changes in the DNA sequence.’ It is called epigenetics.

Genetic evolution usually takes a long time –often a very long time- and circumstances can arise that were not originally anticipated. But there are several mechanisms to silence or inhibit those genes from carrying out their initial instructions and these allow extra opportunities for an organism to survive and adapt to circumstances perhaps not present during its initial evolution. Unfortunately, it can be a two-way street…

Food, food, glorious food -well that’s how I remember the words anyway (apologies to Flanders and Swann). It’s something that is often as pleasant in retrospect as it’s anticipation is in prospect. Something that transcends the here and now. Like culture, it involves feelings and judgments. It is a part of the fabric of our realities, part of the habits that are difficult to change without conscious effort and strong motivation. We wear our preferences as uniforms -identities. Food is not simply what we consume -it reflects a train of thought. There are allegiances, unspoken loyalties that pass from generation to generation. And it is often how others see us -evaluate us. To change or vary, risks awkward questions at the very least. So it’s fascinating to reflect on the importance of food in defining not only who and what we are, but also on it’s influence on what we might become. And what our children might become as a result…

It is not a trifling matter. Food has always had a central role in culture and what a mother eats in her pregnancy has long inspired myths about the child she will deliver. Famines have been instructive: in more recent times, the Dutch Famine of 1944 during World War ll led to intrauterine growth restriction and subsequent chronic diseases such as coronary heart disease later in the offspring’s life.

A similar twist on the importance of prenatal nutrition was highlighted in an article in BBC News: http://www.bbc.co.uk/news/magazine-34222452  ‘.A team from Britain’s Medical Research Council, which has been collecting data on births, marriages and deaths in Keneba since the 1940s, discovered some years ago that in this part of The Gambia when you are conceived makes a huge difference to your chances of dying prematurely.’

This seemingly bizarre finding is corroborated in animal experiments in which, ‘it is possible to make the genes in an embryo more active, or turn them off entirely, simply by varying their mother’s diet.’ And indeed, as the author explains, ‘the studies done in The Gambia certainly provide compelling evidence that these so-called “epigenetic changes” may also happen in humans in response to a change in diet. That if, during very early development, a mother eats a diet rich in leafy green vegetables, then this will change forever just how active some of her child’s genes are.’

There are other epigenetic ramifications that are also important: this ‘happens through a process called methylation and researchers in The Gambia have recently shown that babies conceived in the wet season have very different levels of activity of a particular gene that’s important for regulating the immune system. As Matt Silver, part of the MRC team, says: “Variation in methylation state in this gene could affect your ability to fight viral infections and it may also affect your chances of survival from cancers such as leukaemia and lung cancer.”

Prenatal influences are far greater than we had ever suspected; we were naïve indeed to feel that the importance of diet was primarily to provide nutrients for the developing fetus -ingredients for the recipe. We were too narrow in our conceptions. Too dull, maybe. There is so much about the world –about ourselves- that we are only beginning to understand. We truly live in exciting times… and yet it has always been exciting times for those interested enough to open their eyes hasn’t it? We’ve always lived at the edge of some river or other. It merely takes someone curious enough to travel down it. As Shakespeare said: We know what we are, but know not what we may be.