What’s the big deal about epigenetics?

epi- | ˈɛpi | (also ep-) prefix 1 upon: epigraph. 2 above: epicontinental. 3 in addition: epiphenomenon. ORIGIN from Greek epi ‘upon, near to, in addition’.

Genetics seems to be part of the public consciousness. We are sensitive to discussions about GM crops or animals; we say that our innermost convictions or tendencies are ‘in our DNA’. Genomics and genomes are themselves quite commonly discussed, either in terms of testing or, recently, in terms of editing. DNA is, quite literally, everywhere. The Nuffield Council on Bioethics has recently published several reports in which genetic themes loom large (see, for example, genome editing and non-invasive prenatal testing). So, a recent Council workshop dedicated to the topic of epigenetics was an interesting contribution to the wider discussion of ethics in the context of human biology, health and imagined futures.

As the dictionary definition above
indicates, the prefix ‘epi’ refers to something that lies above or upon an
existing structure, offering an additional layer of complexity or content. Whilst
even scientists might disagree about the best definition of ‘epigenetic’, it is
generally used to refer to the way in which genes and genomes can undergo functional changes that are not
associated with changes in DNA sequence. Most commonly, we mean changes either to
the chemical structure of DNA – such as DNA methylation (DNAm) – or the
structure of the histone proteins that associate with DNA in chromatin. Such
chemical changes, or ‘marks’ as they are sometimes known, can act as additional
layers of information, reflecting the changing activity of genes. It is not always clear whether they are
causally responsible for such activity states, or are by-products. Much depends
on context. But scientists can now study the complex and dynamic changes to
such marks in a genome-wide fashion – characterising what is known as the ‘epigenome’
– using new technologies. And these have yielded interesting insights into gene
regulation in basic research and, more recently, associations between
epigenomic variation and human health.

The workshop was divided into two main sessions.
The first addressed the use of epigenomics tools to examine a number of
phenomena, with several scientists giving brief scene-setting talks. There are a
number of groups aiming to identify changing epigenetic biomarkers, or
signatures, of ageing, characterising so-called ‘epigenetic clocks’. Related
studies aim to establish whether epigenomic signatures may be predictive of the
risk of subsequent disease and there are convincing data that this may be the
case with smoking-induced cancers. These studies are often based on the
examination of DNAm in peripheral blood cells (PBC), a tissue not obviously implicated
in any causal mechanism leading to pathologies in tissues such as the lungs;
but a PBC epigenomic signature can be viewed as a proxy for epigenomic events
elsewhere that are causal and mechanisms
have been proposed to account for this. As ever, more data are required. We
heard claims that epigenomics can be used to infer an epigenetic age that allows
the estimation of ‘time-to-cancer’, ‘time-to-coronary heart disease’ and even
‘time-to-death’. Whilst it is possible that such epigenomic tests could
indicate the degree of risk faced by an individual, and could be useful for
prompting changes in lifestyle, it is also possible that they may be unreliable,
due to the relatively small size of any effect, and may cause unnecessary
anxiety. These are, of course, themes recognisable in the context of discussions
of genetic testing.

We returned several times to a topic
that is of great interest to both scientists and ethicists: the possibility of
transgenerational epigenetic inheritance. Briefly, this is the phenomenon by
which an epigenetic mark might persist over multiple generations, evading
erasure by the normal mechanisms that operate in the germ line and early embryo
to re-set the epigenome and prepare it for subsequent events. What excites many
about this scenario is the possibility that such an epigenetic mark might be
established by exposure to some environmental agent i.e. that it might be
acquired during the lifespan of an individual. The use of the word ‘acquired’
brings to mind the ‘acquired characteristics’ evolutionary model of Jean-Baptiste
de Lamarck, and so has a whiff of paradigm-shifting science about it.

The only problem is that evidence for such a phenomenon is scant indeed, at least in mammals, and is widely contested. It has been reported as a mechanism that explains very rare types of inheritance in the mouse, and other studies in rodents suggest that it may mediate the long-term effects of environmental stressors, including nutritional and behavioural. Scientists disagree about the interpretation of such data. In humans, some have claimed an association between environmental stressors, such as famine, and disease in subsequent generations of the individuals exposed to the stress. But these are only associations and other explanations (including genetic) can be offered for them. As ever in science, causality can be fiendishly difficult to establish in descriptive scenarios in which direct experimental interventions are not possible or simply unethical.

It is important to note that the
environment includes both the natural environment and social environment, the
latter characterised by possible impacts from smoking, mobile phone masts and
education policy etc., and this may account for much of the interest in
epigenetics from social scientists. Several contributors at the workshop noted
that if a strong link were to be established between the behaviour of parents
and impaired health of subsequent generations, mediated perhaps by the
transgenerational inheritance of acquired epigenomic signatures, there was the
prospect of increased guilt on the part of individuals who could have avoided
such behaviour. On the other hand, one potentially attractive feature of
epigenomic states is that, unlike the relative stability of DNA sequence, they
may not be permanent. If somehow reversible, the possibility opens up of an
improvement in the health prospects of any individual with the undesirable
epigenomic signature.

The second session was dedicated to
ethical questions arising from epigenetic technologies and their application in
real-world situations. We heard of epigenomic data being used as evidence in
court cases (guilt has psychological and legal connotations); of studies of
epigenomics in the education setting, perhaps as a way of assessing the impact
of education policy on individual children, acting as a proxy for educational
attainment. These uses of epigenetic biomarkers raise many questions, including
whether such data might ultimately be used to classify individuals in some
deterministic fashion, actually restricting their horizons rather than opening
them up. It would be ironic if ‘genetic determinism’ were to be replaced by
‘epigenetic determinism’ as something to avoid in public policy.

The relationship between genetics and
epigenetics, similarities and distinctions, was a constant theme. Most
acknowledge that these two causal factors in our biology will interact in
complex ways and it will not be easy to disentangle their contributions to our
health, disease and longevity, echoing the similarly complex interaction
between ‘nature and nurture’. How we think about genetics and epigenetics in
the ethical setting is also an interesting challenge. One such setting concerns
traditional ethical objections to purposeful alterations to the human germ line;
in particular, inheritable edits of the human nuclear genome. One workshop contributor
noted that such objections are often based on concerns about the
unpredictability of the consequences of such genomic interventions (broadly,
safety), and on their persistence over multiple generations in individuals who
did not consent to their introduction. But such concerns arise in all instances of human inheritance
conceived more broadly. These could include changes to nutritional advice in
the public health sphere, evolution of education policy or even planning of the
built environment. In all these cases there is the possibility, at least
according to some experts, of such environmental impacts causing inheritable
effects on the epigenome of affected individuals that might persist across
generations, with both direct and indirect negative consequences for
individuals and society more generally. And, of course, in all cases there are
highly likely to be consequences that are similarly persistent, i.e.
inheritable, but that are transmitted culturally.
When inheritance is considered in this broad sense, we can see that ‘germline
genome editing’ does not obviously raise any special ethical concerns that are not already raised by a myriad of
ways in which we attempt to influence or direct human futures.

There was a clear sense at this workshop
that hype – ‘epigenohype’, perhaps – is something to avoid. This requires
better communication, by scientists and ethicists. Much more research is
required to determine whether trans-generational epigenetic inheritance is a
reality in humans. More research is also
needed to establish the robustness and reliability of epigenomic signatures as predictive
biomarkers of human health and disease. Some expert scientists remain sceptical
of their utility. But nevertheless, there is
an epigenetics industry. We learned of ‘epigenetic pancakes’, ‘epigenetic yoga’
and ‘epigenetic shampoo’. So, it seems there may be a bigger conversation to be
had about the societal impact of epigenetics, whether it is always based on
sound science or not. Epigenetics could
be a big deal.