6. Epigenetics

Why would we include an introduction to the ethics of epigenetics in an introductory bioethics textbook? Is epigenetics not a highly technical specialization of biology, hardly accessible to undergraduate students coming to bioethics from other disciplines? We hope to explain the basics of epigenetics in a simplified, understandable fashion in this chapter, because an ethical discussion of epigenetics may be illuminating for bioethics students in at least two ways:

• Epigenetics is an interesting case study to discuss the social and ethical implications of scientific progress in a domain that shows an intricate connection between our body and our environment, or our biology and our biography.
• It allows us to demonstrate that scientific research projects are never value-neutral: in the case of epigenetics, findings can be employed to bolster a wide variety of claims with regards to individual or societal responsibilities, and the priorities of the research also reveal what societies value and want to prevent.

Epigeneticists do not study changes in DNA itself but rather mechanisms that influence how and when genes—which are stretches of DNA bases—are expressed in an organism. Epigenetic mechanisms can affect the transcription and translation of genes in various ways. Two important processes are histone modification and DNA methylation.

• Histone modification: The histone is a kind of spool made of proteins around which the genomic DNA is wrapped to save space. The complex of the DNA and the histone proteins is called chromatin. How tightly the DNA is wrapped around the histone influences how easily the DNA can be accessed and thus copied. The more tightly packed it is, the less gene expression is possible. Tightly-packed and thus less accessible parts of the chromatin are called heterochromatin. The more readable parts are called the euchromatin—genes can only be expressed when they are located here.
• DNA methylation: This epigenetic mechanism involves the addition of a methyl group to a DNA molecule. This does not change the DNA itself, but it does influence whether certain parts of it can be read and transcribed. We can think of DNA methylation as a process to ‘silence’ genes by making them inaccessible.

By regulating gene expression, epigenetic processes influence cell types and tissues phenotypes (observable characteristics), function, and developmental state. Firstly, epigenetic programming is responsible for the differentiation of stem cells into specialized cells, providing them with the ‘memory’ of their differentiated identity. This explains how all cells in an organism contain the same DNA while still performing a wide variety of functions. Each of the ~400 tissues of the human body, for example, has a different epigenome (i.e. a different set of epigenetic modifications), whereas all the cells share a single genome, usually.

In addition to its function in cell differentiation, epigenetics also has other functions throughout the lifetime of an organism. One way in which our epigenome changes is the ‘epigenetic drift’ associated with aging. In general, more epigenetic changes indicates older age, meaning that epigenetic marks can be seen as biomarkers of aging. However, our epigenome changes mostly in response to environmental stimuli, which are most relevant for ethical perspectives on epigenetics. Mechanisms such as DNA methylation can be triggered by environmental factors, both stemming from within the body and from the outside environment. Crudely put, this means that the material and psychosocial circumstances of our body—our diets, the quality of the air we breathe, and the stress we experience—can impact epigenetic mechanisms. This is why epigenetic mechanisms are often treated as missing links between our lifestyle/environment and our physical/mental health.

Epigenetic information can be regarded as another layer beyond genomic information, enriching but also challenging more traditional understandings of genetics. For example, it challenges the ‘central dogma’ of molecular biology which assumes that genetic information flows only in one direction, when DNA is transcribed into RNA which is in turn translated into proteins that determine the phenotype. Epigenetics shows that the interface between genes and their environment is much more complex.

Epigenetic inheritance

Can the epigenetic marks that someone accumulates due to environmental exposure and lifestyle be transmitted to subsequent generations? This question has been intensely discussed and has led to much speculation and ethical theorizing in the past two decades. Most epigenetic programming is rewritten or reset between generations, but there is increasing evidence that this is not always the case. When considering the transmission of epigenetic marks between generations, we need to distinguish between transgenerational and intergenerational effects.

Intergenerational epigenetic inheritance refers to epigenetic marks in offspring that are the result of direct exposure of their parental germline (sex cells) to environmental stressors. This means that intergenerational inheritance is limited to the first generation of male offspring (i.e. children) and the first and second generations of female offspring. Transmission to the first generation of offspring means that epigenetic marks are passed on from one generation to the next (i.e. from parent to child). The second generation of female offspring is also included under intergenerational inheritance because oocytes (egg cells) are already present in a female foetus in the womb. This means that environmental triggers during pregnancy can directly affect not only a first, but also a second generation of offspring.

A famous example of intergenerational epigenetic inheritance occurred during the Dutch Hunger Winter famine of 1944–1945 (Heijmans et al., 2008). The children of mothers who experienced this famine during their pregnancy were found six decades later to have reduced DNA methylation of the imprinted IFG2 gene, which is associated with the risk of metabolic diseases. These and other findings lend empirical support to the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout their lives. Public discourse and research often focuses on maternal factors. However, epigenetics shows that paternal factors and postnatal exposures in later life can play a role in offspring health, in addition to influences in utero. We will come back to this in the final section of this chapter.

Transgenerational epigenetic inheritance is more contested. It denotes the indirect transmission of epigenetic information that is passed on to gametes without alteration of the DNA sequence. As was explained earlier, direct epigenetic inheritance (i.e. intergenerational inheritance) pertains to the passing on of epigenetic information to the first generation of male and female offspring and the second generation of female offspring (since her sex cells were already exposed to external influences in the womb of her grandmother). This means that we can only speak of transgenerational inheritance if the epigenetic effects of the first generation’s environmental exposures are still present in the second generation of male offspring or the third generation (i.e. great-grandchildren) of female offspring. So far, most transgenerational epigenetic effects have been discovered in plants and other-than-human animals such as rats and mice. For example, researchers working with mice have found third-generation epigenetic effects of maternal diet as well as social stress levels, although others argue that multigenerational inheritance of methylation patterns in mice is an exception rather than the rule (Dunn and Bale, 2011; Kazachenka et al., 2018). A study of C. elegans worms by Adam Klosin and colleagues also had impressive results (Klosin et al., 2017). They genetically modified these worms to glow when exposed to a warm environment. The worms not only started to glow more when the temperature was raised, but they also retained their intense glow when researchers lowered the temperature again. Moreover, even seven generations further down the line, glowing offspring were born. If five generations of C. elegans worms were kept warm, this characteristic was passed on to fourteen generations.

Unfortunately, in research on human inheritance, it is virtually impossible to exclude potential confounding elements such as changes in utero and postnatal effects. It is hard to distinguish ‘real’ epigenetic inheritance from cultural inheritance or reconstruction of the environmental context resulting in the same experiences or health problems in offspring. Still, some studies indicate that transgenerational epigenetic inheritance is possible, albeit limited, in humans. Studying historical data of cohorts in Överkalix, researchers found correlations between grandpaternal food supply and the mortality rate of the following two generations, their children and grandchildren (Kaati et al., 2017). Because no molecular data were available, no epigenetic links could be proven. Pembrey and colleagues build on these findings to evidence sex-specific male transgenerational inheritance in humans (Pembrey et al., 2006). In a longitudinal study of men in an area around Bristol, they found transgenerational effects of smoking before puberty on the growth of future male offspring. Specifically, early paternal smoking (before puberty) was associated with a greater body mass index (BMI) in their sons. The researchers posit DNA methylation as a potential mechanism behind those links between the acquired epigenetic traits of a generation and the epigenetic marks present in the next generations.

Diseases, conditions, and cures

The following list is a selection of epigenetic research on various human diseases and conditions. It is not exhaustive, but it is intended to give you an idea of the broad scope of epigenetics research.

• Exposure to stress in the womb or during early childhood has been associated with epigenetically mediated adverse health effects. For example, childhood maltreatment might trigger long-lasting epigenetic marks, contributing to PTSD in adult life. Researchers have found that children of survivors of the 9/11 attack in the USA who were pregnant at the time seem more vulnerable to PTSD and behavioural issues (e.g. Jablonka, 2016). Others argue that epigenetic processes might link the antenatal mood of the mother (e.g. maternal depression) to how infants will respond to new situations (Oberlander et al., 2008).
• As is well known, air pollution has numerous harmful effects on health. Emerging data indicate that exposure to air pollution modulates epigenetic marks (Rider and Carlsten 2019). These changes might in turn influence inflammation risk and exacerbate the risk of developing lung diseases.
• It is well known that lead is a common neurotoxic pollutant that disproportionally affects the health of children. Evidence of the epigenetic basis of the effects of lead is increasing (Wang et al., 2020; Senut et al. 2012)
• The epigenetic mechanisms behind the development of metabolic conditions such as type 2 diabetes, diabetic kidney disease (DKD), and obesity are increasingly well-documented. Like stress, obesity has been posited not merely as a health outcome but also as a causal factor in epigenetics. Paternal prepubescent obesity has been associated with diminished lung function and asthma in adult offspring (Lønnebotn et al., 2022).
• Neuroepigeneticists investigate how epigenetic regulation plays a crucial role in the development and functioning of our brain. Conditions for which epigenetic regulatory mechanisms have been suggested include Parkinson’s, Huntington’s, schizophrenia, epilepsy, Rett syndrome, and depression. Much research seems to be particularly geared towards a better etiological understanding of neurodevelopmental conditions such as Tourette’s syndrome, ADHD, and autism. However, there is still much uncertainty about the concrete causative evidence that might be implicated in the development of such conditions.

Epigenetic changes seem to be more readily reversible than genetic ones. This reversibility holds promising potential for epigenetic therapies for diseases, since epigenetic marks such as methylation patterns can be seen as targets for medical interventions and treatments.

Many clinical research efforts in this domain are directed toward the treatment of cancers. Cancer cells are often characterized by epigenetic drifts, and many tumours are associated with epigenetic reprogramming. While some studies investigate the possibility of epigenetic interventions in general, others focus on specific types of cancer such as breast cancer and prostate cancer. There are many ‘epidrugs’ for cancers in clinical trials, but research on epidrugs for other conditions is also very prolific. Recent projects have aimed to target conditions such as Covid-19, hypercholesterolemia, neurodegenerative diseases, autoimmune diseases such as chronic kidney disease, and depression.

Now that we have a basic understanding of epigenetics, we can start thinking about ethical issues concerning the research field and its findings. There are several aspects to epigenetic findings that we can take into account when thinking about the ethics of epigenetics:

Ethical issues in the literature

Privacy

Exposing inequality

Epigenetics seems to provide new possibilities to map existing injustices as well as the distribution of social and environmental factors that may have a long-term, detrimental effect on people’s health. It is well known that not everyone is exposed equally to external harm. Just look at recent examples in Belgium such as the 3M PFAS scandal—where local residents were found to have elevated concentrations of the toxic chemical PFAS in their bodies—and the Umicore factory in Hoboken—where lead pollution has a big impact on small children (see Case 1 below). Many people also believe that such unequal exposure is, at least in some cases, problematic or unjust. Epigenetic markers could potentially indicate who exactly is hit the most by existing inequalities. And in cases for which we already have an indication—we do not need epigenetics to tell us that people living close to highways suffer more from air pollution—epigenetics might provide new information about the impact on individuals and future generations.

Responsibility

Most normative discussions on the ethics of epigenetics are conducted in terms of distributing responsibility. For example, we can ask ourselves ‘who is morally responsible for the health of current and future generations in the context of epigenetics’?

When we ask who can or should be responsible, we can distinguish between individual, shared, and collective responsibility. The idea of collective responsibility is that a group has certain characteristics that make it a moral agent that can be held responsible. This idea is not uncontested. However, most authors believe that some organizations with a clear structure—such as corporations, governmental organizations, medical organizations, or NGOs—can be said to have some kind of responsibility in the context of epigenetics.

What dimensions of responsibility do we have in mind? We often think about moral responsibility in retrospective or backward-looking terms. We blame people for bad outcomes, or shower them with compliments because they did something with a good outcome. But it is also interesting to think about future-oriented or forward-looking responsibility: how we can attribute responsibility and take responsibility with an eye on what we want to achieve or avoid in the future? When we think about our responsibility for the health of future generations, responsibility can function as a way to distribute moral labour. If we know what state of affairs we want to achieve, we can start thinking about a desirable allocation of the tasks that should be performed in order to get there.

Gunnar Björnsson and Bengt Brülde (2017) created a list of factors which might help to identify moral agents and inform responsibility distribution. This could be useful for distributing responsibility for the epigenetic health of future generations. This is their list:

1. Capacity and cost: The individual or group that has most capacity to produce a good outcome is responsible for doing so.
2. Retrospective and causal responsibility: There is still some connection between what an agent did in the past and who needs to take up responsibility now, even though this is perhaps not as important as other considerations.
3. Benefiting: Benefiting from another’s help or benefiting from harm, injustice, or danger to others can make an agent more responsible, to reciprocate for example.
4. Promises, contracts, and agreements: If an agent promises to deal with a problem, the agent takes on responsibility by doing so.
5. Laws and norms: Laws can prescribe our behaviour and can give direction to and limit our ascribed responsibility.
6. Roles and special relationships: We can have more responsibility towards people we have a close connection to.

Three cases

We may want to ascribe responsibilities to involved individuals and collectives on a variety of grounds and moral principles. As we already saw more generally in earlier chapters, no moral theory can provide a clear-cut answer that points in just one direction here. In short, epigenetic research never holds straightforward implications for healthcare and society. One reason for this is that epigenetic mechanisms in and of themselves are often not sufficient for a disadvantageous outcome. Instead, they always interact with largely pre-existing social, economic, and environmental factors and (dis)advantages. Epigenetic findings alone cannot tell us when a situation is unjust, nor do they provide specific ways to combat situations we do characterize as unjust.

Cautionary approaches

The lifestyles, behaviours, circumstances, and exposures of people who are planning to have a child, or are already pregnant, are indeed subject to intense normative scrutiny in both scientific and popular discourse, but is this fair or just?

Individual and collective responsibilities

Maternal and paternal influences and responsibilities

There seems to be a growing consensus among commentators that the overemphasis on maternal influences in epigenetic risk messaging is unfair because it risks ascribing excessive blame to women. In an influential paper, Richardson and colleagues compellingly demonstrate that narratives about epigenetic findings risk perpetuating “a long history of society blaming mothers for the ill health of their children” (Richardson et al., 2014, p. 131). They give examples from the media such as panic around Fetal Alcohol Spectrum Disorder (FASD) and ‘crack babies’ in the USA, and the popularity of theories about ‘refrigerator mothers’ whose ‘cold’ parenting style supposedly caused autism in their children. They warn us that although the scientific findings underpinning these societal blaming practices are often rather moot or proven to be plain wrong, women still experience the blame to this day.

Thus, researchers should be aware of existing biases and moralizing tendencies in society when they share their findings, in order to minimize the risk that their findings inspire unfair blaming practices. However, the problem seems to be situated on a more fundamental level than the biased language in science communication. The disproportionate attention and resources science has been directing toward maternal influences, specifically in the perinatal period, should also be critically questioned. As we saw earlier in this chapter, ethical considerations also play a role in the construction of epigenetic knowledge itself.

Emancipatory approaches

However, Chiapperino and Testa do not rule out the potential use of empowerment in emancipatory discourse. They refer to a more radical history of the concept, for example in the tradition of liberatory pedagogy. They argue that epigenetic knowledge can be empowering in that it shows people how social factors and environmental exposures can affect their health and that of their offspring. What an empowerment discourse should be mindful of, then, is that people also need to be sufficiently free from financial, social, and material constraints to act on this knowledge.

Parent-child relationship

Take another look at the case of Farah and Alex earlier in this chapter. Might there be any value for the child or the parent-child relationship in having shared knowledge of the lives of parents before they conceived? Or before they were even thinking of conceiving, when their experiences may have impacted the child’s biological make-up nonetheless? If we answer ‘yes’ to this question, we can consider whether epigenetic knowledge has a role to play here. Epigenetic knowledge can perhaps play a contextualizing role, affirming that aspects of the child’s health or personality are not isolated from the actions, behaviours, or exposures of their parents in the past. Consider an example related to environmental pollution:

Jenn and her parents: Two people who intend to have children together have both grown up in a poor neighbourhood close to a polluting factory. They are aware of this pollution and its potential health effects on themselves and their future offspring. Although this is far from easy, they manage to move to another part of their city with relatively clean air. There, they conceive, and their daughter Jenn is born. However, their epigenetic marks from having lived in the polluted neighbourhood may have been inherited by Jenn to some extent.

Would it be valuable for Jenn to know this? And if so, how might she react?

Jenn might be thankful that her parents decided to move away from a place that they were very attached to for her sake. She might gain a better sense of appreciation for their considerations (although it is not unthinkable that she might also feel guilty for being the reason they made such a drastic and costly change). Moreover, knowledge about epigenetic mechanisms might help Jenn understand why she is more prone than others to certain conditions such as asthma. Conversations about the ways in which social determinants of health—conditions in the social and physical environments of people that influence health outcomes throughout their life course—have affected both Jenn and her parents may lead them to a sense of mutual understanding.

In short, the power of epigenetic knowledge might lie in helping people to integrate their biography and their biology. Another way to put this is that parent-child conversations on such topics help the child to create their own narrative identity: it can help parents, children, and families to tell stories about why they are who they are.

Moreover, epigenetic research can help to value the contributions different individuals make towards the upbringing of children. Lesbian mothers who gestate a child conceived with their partner’s oocyte and donor sperm (Bower-Brown et al., 2024) and surrogates (Pande, 2009) often use epigenetic research as biological proof of their meaningful contribution to a child’s being. In queer families, epigenetic effects are used to argue that kinship can be based on other biological connections than mere genetics. Kinship is then seen as connections between people who care for each other every day, whatever the genetic bond between them. In the same way, epigenetic findings allow for a broader understanding of ‘mothering’ as a practice by multiple people: parents and other caretakers, for example day care staff or grandparents. Thus, epigenetic research not only enables multiple people (or the community at large) to be perceived as responsible for a child’s well-being, but also enlarges the web of connections between them. By involving groups of people in kinship in a meaningful way, epigenetic knowledge has the emancipatory potential to queer existing kinship schemes.

In this chapter, we showed various ways in which researchers and students can engage in ethical discussions of developments in epigenetics. After a brief introduction to the scientific background of epigenetics, we formulated several ethically relevant aspects to epigenetic findings that we can take into account when we are considering the moral impact of such findings: the influence of the environment, heritability, unpredictability, and reversibility. We outlined ethical issues which are being discussed recurrently in bioethical literature on epigenetics, and presented readers with a few cases that invited them to ask ethical questions and practice moral reflections, applying concepts and theories. Finally, we discussed two particular issues in more detail: (1) how the case study of epigenetics demonstrates that scientific research projects are never value-neutral, and (2) how research findings can be employed in multiple ethical discourses in the specific debate on the responsibility of (prospective) parents for the health of their offspring.