Published by Oxford University Press on behalf of the International Epidemiological Association
ß The Author 2012; all rights reserved.
International Journal of Epidemiology 2012;41:303–308
doi:10.1093/ije/dys030
Essay Review
Epigenetics for the masses: more than
Audrey Hepburn and yellow mice?
The Epigenetics Revolution: How Modern
Biology is Rewriting Our Understanding
of Genetics, Disease and Inheritance.
Nessa Carey. UK: Icon Books Ltd, 2011, pp. 320,
£17.99, ISBN: 9781848312920.
Epigenetics:
the
Ultimate
Mystery
of
Inheritance.
Richard
Francis.
New
York:
W.W. Norton and Company, 2011, pp. 234, £19.99,
ISBN: 9780393070057.
Epigenetics is going pop(ular): in the recent television
series, Brave New World, hosted by physicist Stephen
Hawking (author of the best selling A Brief History of
Time) the veteran presenter of TV nature and science
programmes, David Attenborough, says, ‘I think the
most significant discovery in the last decade or so has
been the recognition that genetics is not just a matter
of chromosomes’. Attenborough is, of course, a saint,
but pop-science media tarts have identified epigenetics as a niche market, with an audience bored by
the apparent lack of delivery from genetics more than
a decade after the excited announcement of the
sequencing of the human genome. For epidemiologists, invoking epigenetics is one way of establishing
their up-to-the-minute ‘scientific’ credibility as they
make hand-waving statements about potential
causal processes in disease, which can help dispel
the impression of them being overpaid phlebotomists
or (worse) moonlighting statisticians (Figure 1).
The flock of intended-to-be popular books on epigenetics now hitting the market can provide a largely
painless way for epidemiologists to attain instant expertise. One of the earliest off the block is Nessa
Carey, with her take on ‘The Epigenetics Revolution’.1
Carey is a scientist with a varied disciplinary background, and brings unusual rigour to a book intended
for the general reader. It provides a more than basic
introduction to the topic, with up-to-the-minute
coverage of recent developments in the field. Much
of the material overlaps that covered in this special
issue of the IJE, and summarizing this here would
risk being repetitive. Importantly, the starting point
for an epidemiological engagement with epigenetics
is clearly stated:
The majority of non-infectious diseases that afflict
most people take a long time to develop, and then
Figure 1 Epigenetics: the confused epidemiologist’s friend.
Note: Every effort has been made to trace copyright holders,
obtain permission from them and to ensure that all credits
are correct. The International Journal of Epidemiology has
acted in good faith at all times and on the best information
available to us at the time of publication. We apologise for
any inadvertent omissions, which will be corrected as soon
as possible if notification is given to us in writing
remain as a problem for many years if there is no
cure available. The stimuli from the environment
could theoretically be acting on the genes all the
time in the cells that are acting abnormally, leading to disease. But this seems unlikely, especially
because most of the chronic diseases probably involve the interaction of multiple stimuli with multiple genes. It’s hard to imagine that all these
stimuli would be present for decades at a time.
The alternative is that there is a mechanism that
keeps the disease-associated cells in an abnormal
state, i.e. expressing genes inappropriately. In the
absence of any substantial evidence for a role for
somatic mutation, epigenetics seems like a strong
candidate for this mechanism.
The mechanisms of this cellular memory, stable
across cell division, are presented with some helpful,
but simple, figures. The well-known dramatic cases—
such as inactivation of one of the two X chromosomes
in placental mammalian females—are discussed, and
the well established epigenetic processes involved in
human diseases—such as some cases of Prader–Willi
303
304
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
and Angelman syndromes—outlined. In these cases
there is no overstatement and the limitations of current knowledge are made clear, which is unusual in
the genre. As would be expected, the dramatic epigenetic pin ups—genetically identical larvae becoming
either queen or worker bees, how tortoiseshell cats
get their patterning, and maternal licking and grooming lead to stress-resistant adult mice—feature prominently. Again the treatment is restrained. This is seen
in the case of the epigenetic top of the pops, the
yellow (agouti) mice. I am sure I am not the only
epidemiologist who has squirmed with embarrassment as a colleague has discussed epigenetics, unhindered by the constraints of recognized ignorance, and
a slide of a fat yellow mouse—invariably diabetic, we
are told—is shown, next to their sleek, conventionally
coloured, thin and non-diabetic relative. Inadequate
maternal nutrition—in particular, low folate
intake—is said to lead to the disappointing murine
outcome. In clear and ringing tones, extrapolation to
the fetal origins of human disease is made. In contrast in Carey’s book what is known and what is not
known of the mechanism of agouti transmission is
well explained. The fact that the outcome is in no
way deterministic is also acknowledged, with
both the schematic figure (Box) and photograph
(Figure 2) presenting the range of offspring outcomes
that are observed. In general the probabilistic and stochastic nature of some epigenetic events is emphasized, and ‘the power of a random epigenetic event’
given its full due, in keeping with much evolutionary2
and epidemiological3 reasoning.
The establishment of epigenetic marks is fundamental to development; equally the removal of such patterns is essential to the generation of the totipotent
cells in a fertilized zygote. The waves of erasure of
epigenetic modifications during this process are well
described, which makes clear the limited potential
for transmission of epigenetic markers between
Figure 2 Genetically similar mice showing the extent to
which fur colour can vary depending on expression of the
agouti protein. Photo reproduced with the kind permission
of Professor Emma Whitelaw
generations and thus the restricted possibilities of
transgenerational epigenetic inheritance. The best
known animal exceptions—the agouti and kinked
tail (Axinfu) mouse—represent the imperfect transmission of the silencing of probably virus-derived retrotransposons. In general The Epigenetics Revolution is
restrained about transgenerational inheritance, and
does not exploit the transgressive excitement of
embracing Lamarckianism. The limitations of studies
purporting to demonstrate this are discussed, and the
topic occupies a small and proportionate number of
pages of the book. This did not stop a reviewer in the
British Guardian newspaper referring to the ‘everything you’ve been told is wrong’ moment when we
learn that changes acquired during life can be passed
on to the next generation.4 The review elicited a succinct response in the letters column of the Guardian
from the evolutionary biologists Deborah and Brian
Charlesworth, pointing out that:
It is even less likely that epigenetic marks are very
important in evolution. We know this from experiments on genetically identical individuals (which
can be produced experimentally in some organisms, just as multiple cuttings can be made from
the same plant) – these do differ in their characteristics, due to effects of the environment, or
chance, and they differ in the precise epigenetic
marks carried. But breeding from the most extreme individuals, for instance for the largest or
smallest size, has repeatedly been found to produce offspring with almost exactly the parental
range and distribution of characteristics, with
only slight differences that can be accounted for
quantitatively by the small effects of new mutations in the genes. If epigenetically caused differences are transmitted from parents to offspring,
their effects are thus tiny and cannot account for
much of what happens in evolution.5
The Charlesworths explain why transgenerational
epigenetic inheritance is unlikely to be a major
player with respect to phenotypic differences that provide the raw material for natural selection. The same
is true for the health-related traits in a population
that epidemiologists are concerned with. References
in support of this contention, and further discussion,
are provided elsewhere in this issue of the IJE.6 The
subtitle of the book, How Modern Biology is Rewriting
Our Understanding of Genetics, Disease and Inheritance,
might have been anticipated to generate overexcitement in reviewers. In the trade-off between
veracity and marketing the latter usually wins.
I would recommend The Epigenetics Revolution highly
to anyone seeking an introduction to epigenetics. It is
comprehensive in its coverage, generally well written
and introduces basic information and concepts as
they are required, rather than having a tedious ‘genetics 101’ chapter early on in the book, a feature of
ESSAY REVIEW: EPIGENETICS FOR THE MASSES
305
Box The Epigenetics Revolution on agouti mice: Figure and accompanying text
For convenience, the picture only shows the offspring who inherited the Avy retrotransposon from their
mother, as this is the effect we are interested in. If the mother had an unmethylated Avy gene, and hence
had yellow fur, all her offspring also had either yellow fur, or slightly mottled fur. She never had offspring
who developed the very dark fur associated with the methylation of the retrotransposon.
In contrast, if the mother’s Avy gene was heavily methylated, resulting in her having dark fur, some of her
offspring also had dark fur. If both grandmother and mother had dark fur, then the effect was even more
pronounced. About a third of the final offspring had dark fur, compared with the one in five shown.
Illustration from The Epigenetics Revolution by Nessa Carey, ß Icon Books.
popular science books that often leads me to abandon
them prematurely. It gives a sense of both the promise and the challenge of epigenetics in a way that is
useful to people with a peripheral engagement with
the field. It is up to date and the occasional errors
(e.g. it is suggested that techniques for assessing
DNA methylation mistake 5-hydroxymethylated
for unmethylated DNA, whereas the misreading
is to classify both 5-hydroxymethylcytosine and
5-methylcytosine as methylated)7 are at a level of
technicality that means the primary literature would
need to be read before any use could be made of the
concepts. All in all, this is a book to buy and read.
The Epigenetics Revolution does suffer from some of
the limitations of books intended for the pop-science
market, however. As seems de rigueur in the genre, the
scientists are described in ways that make them
appear a favoured lot: they are ‘engaging’, ‘striking’,
‘drily funny’ or ‘terrifically enthusiastic and intensely
rigorous’. She is ‘one of the youngest professors ever
appointed’, whereas he ‘carries his prestige very
lightly, despite his status’ or is a ‘trim, neat,
clean-shaven American who looks much younger
than his 60 years and is exceptionally popular
amongst his peers’. Dismayingly for the tonsorially
challenged among us hair seems a particular focus;
he has ‘curly grey hair and a frankly impressive
moustache’, a ‘wonderful head of swept back blonde
hair’ or is ‘tall, thin, tanned and with thick
close-cropped white hair’. This golden bunch seem
very different to the pen portraits that one could imagine for an attempted popular book on epidemiologists: ‘a lecherous wizened homunculus’ or ‘like
Margaret Thatcher on acid’ come to mind.
The glorification of individual scientists in the popular science trade is often coupled with a desire to give
individualized illustrations of general points. In The
Epigenetics Revolution the exemplar is the movie star
Audrey Hepburn. As a child (Figure 3) Hepburn
lived through the privations of the Dutch Hunger
Winter, when a German blockade led to famine conditions in parts of Holland. Studies based on people
in utero during this catastrophe have suggested
long-term influences on adult disease risk, and some
transgenerational influences on their reproductive
outcomes have been reported. For Audrey Hepburn,
who was a teenager during the hunger winter, we
are told that ‘the after effects of this period, including
306
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Figure 3 Audrey Hepburn 1939—aged 10. Courtesy of
Audrey Hepburn Estate collection copyright ß Sean Ferrer &
Lucia Dotti. Photograph by Manon Van Suchtelen
Figure 4 Audrey Hepburn with her son Sean in Rome:
enjoying a cigarette but not appearing to appreciate the
presence of the paparazzi. Luciana’s Press Photo/Rex
Features
poor physical health, stayed with her for the rest of
her life’. This story was picked up by the British Daily
Mail newspaper in a review of the book entitled ‘Is
Audrey Hepburn the key to stopping the obesity epidemic?’.8 The answer is, of course, no. The Dutch
Hunger Winter literature and theorizing regarding
the supposed epigenetic influences of this event are
largely based on those exposed in utero; Hepburn was
a teenager. Hepburn died of abdominal cancer,
probably originating in the appendix, and there is
no evidence of an increase in cancer risk (except
possibly breast cancer) following exposure to the
hunger winter at the age at which she experienced
its effects.9 And even if there was evidence of a probabilistic increase in risk of some outcome that
Hepburn suffered from among groups exposed to
the hunger winter in childhood—for example, her
history of miscarriages could be related to the adverse
effects of such exposure on reproductive function10—
this cannot of course be taken to explain an individual case3, and such individual attribution would also
not be compatible with the respectable 9.5 lb birthweight of her son, Sean.11 So many other aspects of
Hepburn’s life course could be appealed to: she was
said to have been of fragile health from birth, her
mother was not affectionate, her parents divorced
and she was sent to a traditionally dire British private
school (where she first developed her lifelong
migraines) before returning to Holland to avoid her
mother’s worry that the Nazis would invade Britain
(in retrospect a poor decision). Her ill-health existed
before and persisted through the famine and caused
concern throughout her career; for example she was
ill when over working in the scalding summer heat
filming Roman Holiday in 1952. She was a smoker
(Figure 4). The attribution of a trajectory of poor
health that started before the famine to that particular experience looks rather shaky. The more important
point, and of relevance to such personalized stories
beloved of popular science books, is that the very
notion of making individual attributions in such cases
is fundamentally misguided,3 and gives a misleading
impression of what can and cannot be known.
Audrey Hepburn is something of an anomaly in The
Epigenetics Revolution, whereas Richard Francis’
Epigenetics: the Ultimate Mystery of Inheritance is full of
such singular stories.12 It starts with a pair of
ESSAY REVIEW: EPIGENETICS FOR THE MASSES
identical twins who differ dramatically in the severity
of their Kallmann’s syndrome, but has some very
tenuous tales. An extended six-page summary of the
movie The Deer Hunter is used to introduce posttraumatic stress disorder, which is then somehow linked
to our old friend the chilled-out licked and groomed
mouse. Audrey Hepburn was at least a real person, a
movie star rather than a movie character. Other such
stories follow: the fat ‘friend’ in Bangkok (programming in utero?), George Washington and the founding
of the American mule market (parent of origin
effects?), etc. The story of the cloning of the first
cat is more engaging: the owner wanted to recreate
their beloved cat, Rainbow, but being a tortoiseshell
cat the random X inactivation led to a feline of rather
different appearance.
Although giving a more discursive coverage, Francis’
book does not generally oversell epigenetics (despite
again having a subtitle that suggests it might) and,
refreshingly, devotes more space to Sewall Wright
than Conrad Waddington. For readers wanting more
detailed and technical material to back up the somewhat impressionistic coverage there are detailed notes
and references (constituting a quarter of what is a
short book). The summary chapter extracts four well
chosen themes: epigenetic processes as developmental gene regulation; as mediators between the
environment and phenotype; as mechanisms for the
random elements of development; and as portals for
transgenerational inheritance (but with the caveat
that the role of this in mammals is limited). Finally
there is a meta-theme, of genes having two aspects,
one as causal agents and the second as responsive
semi-improvising actors in a play in which ‘genomic
activity is as much effect as cause during cellular differentiation, both normal and pathological’.
The tendency to personalize aside, these two books,
early examples of pop-epigenetics, generally refrain
from overstatement and wild claims. This is more
than can be said for news stories accompanying the
online publication of one of the papers in this issue of
the IJE.13 A study in Scotland demonstrated a social
gradient in global DNA methylation of white blood
cells among adults. Interesting: but the headline in
The Scotsman newspaper read ‘Babies born into poverty
are damaged forever before birth’.14 A study only
examining adult DNA apparently showed that genes
‘were found to be affected within the first few weeks
of an embryo’s development’. According to the
newspaper report the researchers, ‘experts in epigenetics . . . believe factors experienced by expectant
mothers in areas of deprivation cause bugs to develop
in the DNA of embryos, with the children more susceptible to early onset of diseases when they become
adults’. Despite having no data from before middle
age the newspaper reports that the researchers
thought it ‘very likely that the significantly lower
levels of methylation we’re seeing in the most
deprived area of the city are set before birth’. Surely
307
the journalists are to blame here? The paper published
in the IJE, correctly, reads ‘This cohort does not present sufficient data points to determine whether fetal
programming plays a major role, this would require
further investigation in a larger study’.13 This is all
very restrained and scientific. In the press release
that his institution issued to accompany the paper,
however, the senior author is directly quoted as
making the statement that ‘it’s very likely that the
significantly lower levels of methylation we are
seeing in the most deprived areas of the city are set
before birth’,15 which is (as so often) just copied
straight into the newspaper report. It is no wonder
The Scotsman refers to ‘bugs in the DNA’, and what
a missed opportunity for enhancing rather than
undermining public understanding of science. Such
nonsense is enough to make an academic journal
editor’s heart bleed, and have more respect for the
relatively restrained nature of at least some popular
science writers.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
Carey N. The Epigenetics Revolution: How Modern Biology is
Rewriting Our Understanding of Genetics, Disease and
Inheritance. UK: Icon Books Ltd, 2011.
Martin GM. Epigenetic gambling and epigenetic drift as
an antagonistic pleiotropic mechanism of aging. Aging Cell
2009;8:761–64.
Davey Smith G. Epidemiology, epigenetics and the
‘Gloomy Prospect’: embracing randomness in population
health research and practice. Int J Epidemiol 2011;40:
537–62.
Forbes P. The epigenetics revolution by Nessa Carey. The
Guardian, 19 August 2011.
Charlesworth D, Charlesworth B. Not quite a revolution.
The Guardian Review, 3 September 2011, p. 15.
Davey Smith G. Epigenesis for epidemiologists: does
evo-devo have implications for population health research
and practice? Int J Epidemiol 2012;41:236–47.
Huang Y, Pastor WA, Shen Y, Tahiliani M, Liu DR, Rao A.
The behaviour of 5-hydroxymethylcytosine in bisulfite
sequencing. PLoS ONE 2010;1:e8888.
Naish J. Is Audrey Hepburn the key to stopping the obesity epidemic? Daily Mail, 4 February 2012.
Ellias SG, Peeters PHM, Grobbee DE, van Noord PAH.
The 1944–1945 Dutch famine and subsequent overall
cancer incidence. Cancer Epidemiol Biomarkers Prev 2005;
14:1981–85.
Elias SG, Noord PAH, Peeters PHM, den Tonkelaar I,
Grobbee DE. Childhood exposure to the 1944–1945
Dutch famine and subsequent female reproductive function. Human Reprod 2005;20:2483–88.
Karney R. A Star Danced: the Life of Audrey Hepburn.
London: Bloomsbury, 1993.
Francis R. Epigenetics: the Ultimate Mystery of Inheritance.
New York: W.W. Norton and Company, 2011.
McGuinness D, McGlynn LM, Johnson PC et al.
Socio-economic status is associated with epigenetic differences in the pSoBid cohort. Int J Epidemiol 2012;41:
151–60.
308
14
15
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Mclaughlin M. Babies born into poverty are damaged
forever before birth. The Scotsman, Tuesday 24 January
2012.
University of Glasgow research shows health inequalities
imprinted on DNA; http://www.glasgowcityofscience.com/
index.php/news/99-university-of-glasgow-researchshows-health-inequalities-imprinted-on-dna.
GEORGE DAVEY SMITH
MRC Centre for Causal Analyses in Translational Epidemiology,
University of Bristol, Bristol, UK
E-mail: [email protected]
Published by Oxford University Press on behalf of the International Epidemiological Association
ß The Author 2012; all rights reserved. Advance Access publication 8 February 2012
International Journal of Epidemiology 2012;41:308–309
doi:10.1093/ije/dyr235
Book Review: Epigenetic Epidemiology
Epigenetic Epidemiology. Karin B. Michels (ed). New York: Springer,
2012, pp. 439, £135.00, ISBN-10: 9400724942; ISBN-13: 9789400724945
Epidemiology has evolved over recent decades to embrace the increasing interest in molecular events that
contribute to our health and disease. The latest of
these to join the ranks is ‘Epigenetic Epidemiology’.
Epigenetics is a discipline that is long established
but has largely been confined to the realms of developmental biology and tumour biology and only
recently have investigators come to turn their attention to population-based studies of epigenetic patterns. The merging of epidemiology and epigenetics
brings with it many challenges. This textbook aims
to highlight both the challenges and opportunities of
this synergy. It aims to be both a primer in epidemiology for epigeneticists and an epigenetics reference
for epidemiologists.
The first section of the book, consisting of chapters
1–5, aims to provide a foundation for both disciplines.
It begins with a general introduction to the human
epigenome, covering the what, where and how of epigenetics. It describes the different types of epigenetic
mechanisms, how they are brought about and maintained and the role they play in normal and abnormal
cell function. Considerations regarding planning and
design, laboratory methods, biostatistical approaches
and interpretation of epigenetic epidemiological studies are subsequently discussed. This section provides
a broad (occasionally slightly repetitive) introduction
to anyone embarking on experimental and/or epidemiological research in epigenetics and can be read
as a standalone text. In addition, it provides a solid
grounding for the subsequent sections of the book.
The latter chapters appear somewhat brief at first,
especially with regards to the epidemiological components, providing a general introduction rather than an
in-depth discussion. However, they do deliver a broad
overview, making the reader aware of the major
issues impacting on epigenetic epidemiological studies
from the planning stage right through to evaluation
and presentation of results. The text is well referenced
with current literature, enabling the reader to further
research any issues pertinent to their specific interests. As is the case in all rapidly moving fields of
research, however, the methodological chapters have
the unavoidable potential to date quite rapidly as new
technologies and analysis methods are developed and
incorporated into the field. Nonetheless, the biostatistics chapter is particularly useful, providing an easy to
follow description of possible analysis options, good
references and a helpful section on available statistical
software, which will appeal to both epidemiologists
and epigeneticists alike. One key issue that has been
missed, however, involves the concerns surrounding
pre-processing of methylation data. As yet no definitive protocols have been established in the research
community making comparisons between studies difficult. Normalization of data, for instance, is only
briefly touched on in the text and more information
on this issue would have completed this section
nicely. Readers can perhaps glean this information
elsewhere from the emerging literature in this field.
The second section, chapters 6–12, delves deeper
into the discipline of epigenetics. The section is structured in such a way that it highlights the key
sub-specialities and active areas of research while
capturing several key concepts within the field of epigenetics. Specifically, these concepts include the development and maintenance of the epigenome, the
architecture of the epigenome using data primarily
from twin studies, the role of imprinting and known
disorders arising from abnormalities in epigenetic
regulation, putative effects of assisted reproductive
technology (ART) on the epigenome, recognized determinants of epigenetic variation (both genetic and
environmental) and finally the potential role of epigenetics in complex disease pathogenesis. This section builds nicely on concepts introduced in the first
section. Each chapter in itself is a standalone text
that does not need to be read in sequence. However,
collectively, these chapters provide some interesting
insights into the different sub-specialities within epigenetics research. Several chapters give well-rounded
perspectives of the subject areas, utilizing a mixture of