This sounds like crazy myth, not cutting-edge science: your asthma is your
grandmother’s fault – for smoking. Your weight issue is because
Great-Grandpa Harry was raised in poverty and taught to grab any crumb he
could. Your depression is the result of a long-dead relative’s fears. You
inherited their problems long before you were conceived, but that doesn’t
get you off the hook. How you live will affect your children’s children.
Your own unhealthy lifestyle is putting future generations at risk.
Genes come into all of this, but they are only half the story. There’s a
mysterious mechanism that acts upon your genes so that, at best, you turn
into the fittest, most efficient machine you can be in your environment. At
worst, you get ill or miserable, or both. A growing number of scientists are
convinced that it’s when this mechanism goes awry that we see the strange
new epidemics of obesity and other “lifestyle diseases” that are sweeping
the modern world.
We can see the mechanism at work to good effect in the animal kingdom.
Honeybees decide when they are still larvae whether to develop into a queen
or a worker, based on a prediction about the role they’ll play in the
colony. How do they know? Another bizarre fact: there is a meadow vole that
is born with a thicker coat in winter. And a species of locust that develops
without functional wings if there is likely to be lots of food and little
competition in the world. But if the signals it receives in the egg suggest
high population density and lots of competition, it will develop wings that
can carry it far to forage. The two have identical genes, but look so
different that for a long time biologists believed they were separate
species.
The phenomenon responsible is “foetal programming”, a dynamic interaction
between genes and environment intended to give creatures the best chance of
survival. Until recently, says Professor Peter Gluckman, a specialist in
foetal development at the University of Auckland, New Zealand, “no one
thought these kind of adaptive responses had any relevance to human biology.
They were just oddities of the zoo”.
If you haven’t heard of epigenetics – meaning “on the genes” – you soon will.
Epigenetics is the mechanism by which chemical switches affect the activity
of genes, turning them on and off or toning down what they do, without
changing the DNA structure. Every living organism has a basic epigenome, an
“instruction manual” controlling the functioning of the genes. During our
lives the manual is edited, gaining and losing instructions as we interact
with our environment.
Until recently, epigenetics was an esoteric backwater of human biological
research, eclipsed by our “fixation” with genes, says Gluckman’s research
partner, Professor Mark Hanson of Southampton University. “The discovery of
the structure of DNA in 1953 made everyone think, ‘Oh, now we’ll have the
blueprint for life.’ There was such a push to find the mutations that might
link to shoplifting, smoking, homosexuality, cancer, or whatever, that we
got derailed.”
The failure of the Human Genome Project, completed in 2003, to deliver all
that was expected of genetics led researchers to look even deeper for clues
to what makes us who we are and what goes wrong in disease. Epigenetics is
now at the cutting edge of medical science.
Gluckman and Hanson’s interest in this field, particularly in “foetal
programming”, was sparked in the early 1990s by the work of Professor David
Barker, an epidemiologist from Southampton University, who had discovered a
link between being born small and suffering from high blood pressure,
stroke, heart disease and diabetes in later life. Gluckman, Hanson and
others have gathered data suggesting conditions in the womb send signals to
the human foetus about the environment it will be born into, which influence
the way its biology is set.
Unfortunately, the tools evolution has given us to match us to the world we
live in can’t keep pace with modern life. “Those mechanisms were established
before we had agriculture, density of settlement, cars and McDonald’s,” says
Gluckman. “We’ve changed the world too far and fast for our biology to
cope.” For example, many of us, he believes, are hard-wired to make the most
of available calories – and to prefer fatty foods – in expectation of a more
frugal world than we actually find. It’s a radical concept, for it means
that the fact that so many of us are overweight and suffering from diabetes,
heart disease, clogged arteries and the like may not be entirely down to
greed. Your weakness for cream cakes could be a misguided biological
survival strategy beyond your control.
The long-term effects of a mismatch between the predictions in the womb and
the world we live in – first highlighted by Barker’s small-baby data – are
most obvious in people who change suddenly from a traditional to a modern
way of life, says Jonathan Seckl, professor of molecular medicine at
Edinburgh University. Seckl has been working with the San people in South
Africa, nomadic hunter-gatherers who have only recently settled in urban
areas. “When people in poor rural circumstances – where the diet is
borderline, survival is precarious, and stress and exercise levels are high
– move to the city, where food is plentiful and they don’t have to hunt it
or grow it, you see an awful lot of obesity, diabetes, high blood pressure
and heart disease,” he says.
Developmental biologists have long assumed that when sperm meets egg, the
epigenetic slate is wiped clean in the embryo. Now this principle is taking
a battering, as evidence mounts that environmental effects can be
transmitted between generations without any changes in the genes themselves.
Last year, researchers in California reported a link between women who smoked
while pregnant and asthma in their grandchildren. Researchers studying
records dating from the 1890s of a rural community in Sweden found that men
who had been well nourished before puberty were four times more likely to
have grandchildren who died of diabetes than those who’d grown up hungry.
The same researchers, studying the lifestyles and biology of about 14,000
people living around Bristol, found a link between men who smoked before
puberty and the tendency of their sons to get fat in childhood.
What could explain these correlations? The timing of events is critical:
puberty is when the developing sperm are most sensitive to environmental
influences. And eggs develop in women when they are foetuses in their
mothers’ wombs. The inference is that the epigenetic slate is not wiped
clean between the generations: some memory remains in the foetus’s DNA of
the environment in which the sperm and egg first emerged. Gluckman, Hanson,
Seckl and others have shown this to be so with rodents, but it has yet to be
proven in humans.
Nobody knows what the environmental cues are that trip the epigenetic
switches. “That’s the 64-billion-dollar question,” says Seckl. But they do
know how epigenetic “marks” are laid down. One way, “methylation”, involves
chemical tags being attached to our DNA at key positions. The tags stop that
bit of the DNA code being read, “silencing” those genes. Now groups in
Europe and the US have begun the ambitious task of mapping the human
epigenome.
“The consensus is building that the largest non-genetic contribution to most
common diseases is going to be epigenetic, because that is the way every
single exposure to the environment can leave its mark on the genome,” says
Dr Stephan Beck, who leads the mapping team at the Sanger Institute in
Cambridge. “I call epigenetics the missing link between genes, disease and
environment.” He says that once we know what the epigenome is like in
healthy tissue, we’ll be able to see what goes wrong in diseased
tissues. “Having the reference will open up the investigation to literally
all diseases.”
And it’s not just our physical attributes that are formed under the influence
of epigenetic factors. There are new clues to the causes of mental illness –
an area of medicine in which studying genes alone has been particularly
fruitless, even though mental illnesses clearly run in families.
In New York, the psychologist Rachel Yehuda has run a clinic for Holocaust
survivors since the early 1990s. Surprisingly, the people who came in
greatest numbers were not the survivors themselves but their offspring,
suffering the same anxiety and mood disorders as their parents, even though
they had not experienced the original horror. “As one person put it, ‘The
most important thing in my life happened before I was born,’” she says.
Her patients described being preoccupied with escape routes in new buildings,
or assessing whether strangers would hide them from persecution if
necessary. What was going on? Yehuda’s interest was piqued by experiments
with rats showing that the way pups are handled as newborns has a dramatic
effect on their stress response, hard-wiring it for life. She believed she
was seeing something similar in her patients – a reaction to events governed
not by genes but by the environment in which they were raised.
Proving it has been impossible. “The argument’s always been that the offspring
of survivors get vicariously stressed by listening to the awful stories from
Mum or Dad,” says Seckl, Yehuda’s research colleague. “But you can’t take it
much further because the Holocaust was a long period of exposure and a long
time ago.”
But 9/11 – a cataclysmic and recent event – has provided a unique opportunity
to look at how and when stress responses are set. Yehuda was one of many
mental-health experts drafted in to provide counselling for traumatised New
Yorkers. Her patients included a woman whose car windscreen was hit by a
falling body, and one who was a waitress in the restaurant next door when
the World Trade Center fell.
A big surprise, she says, was that there were fewer traumatised people than
the authorities expected. Why could some cope emotionally with such horrors
while others crumpled? Could stressful events experienced by the parents of
those who did become ill have primed them to be vulnerable to trauma
themselves, as was the case with the Holocaust survivors’ children?
To try to answer such questions, Yehuda and Seckl are working with a group of
187 women who were pregnant at the time of 9/11 and who were very close to
Ground Zero. A year after birth, the babies of mothers who suffered
post-traumatic stress disorder (PTSD) were found to have levels of stress
hormones indicative of high anxiety. “You could say the mothers are
genetically prone to become stressed and have passed those genes on to their
babies; or they behave differently as mums because they’ve got PTSD and the
babies are picking it up subliminally,” says Seckl. “But what makes us think
this is foetal programming is that it really only occurred in mothers who
were in the last three months of pregnancy.”
Animal studies show there are periods for the developing foetus when different
organs and body systems are susceptible to environmental influence; outside
those periods they aren’t affected. But Yehuda stresses that more research
is needed before they can pin down exactly what happened to the 9/11 mothers
and their babies.
So too for scientists trying to explain another mental-health conundrum: a
link between starvation and schizophrenia. Evidence comes from health
records of survivors of two famines of recent history: the “Dutch hunger
winter” of 1944-5, when the Nazis cut food supplies to Holland; and the
famine in China during Mao’s Great Leap Forward of 1959-61, which claimed
about 30m lives. Researchers have found that people whose mothers were
starving while pregnant are twice as likely to suffer from schizophrenia as
the mainstream population.
While these researchers focus on how nature and nurture interact through
epigenetic processes, others are trying to understand the basic “instruction
manual” that everyone needs in order to grow into a mature individual, and
to ensure that all the different cell types – such as skin, bone, liver,
heart – remember what they should be every time they divide. Here too
extraordinary things are being revealed – and some old mysteries solved.
One such mystery involves two rare brain disorders. Prader-Willi syndrome
(PWS) is characterised by poor muscle tone, a voracious appetite and a
tendency to become obese. The cause of PWS – faulty genes on chromosome 15 –
was discovered in the 1980s. But the researchers were in for a shock, for
they found that the same genetic defect was responsible also for Angelman
syndrome, a different brain disorder, characterised by jerky movements, a
smiling appearance and very little speech.What could account for two such
distinct manifestations of the same genetic fault?
Humans have 23 pairs of chromosomes (little strings of DNA that carry the
genes) in all our cells, with half of each pair inherited from each parent.
And it turns out that for a number of genes, it matters very much which
parent they come from. The first inkling of this came in the mid-1980s, when
scientists in Cambridge created mouse embryos in which the full complement
of genes came either from a sperm or an egg, and implanted them in a mother
mouse. The surprise was that the embryos (which were not viable for long)
developed very differently, depending on whether the genes came from the
male or female.
This was dynamite, says Professor Wolf Reik, the molecular biologist whose job
it became to tease out what was happening. “At that time there was no known
gene that behaved like that.” Reik, now at the Babraham Institute,
Cambridge, is at the forefront of research into “imprinted genes” – those
with a sex bias. Around 80 such genes have been discovered so far. Each has
been marked with an epigenetic “tag” that dictates which copy, male or
female, is to be active and which silenced in the developing embryo. It
appears that the faulty genes that cause Prader-Willi and Angelman syndromes
are imprinted genes. And the crucial difference in the outcome for the child
is whether the defective genes are inherited from the mother or father.
But why are genes from our parents silenced in the first place? Most imprinted
genes have something to do with controlling the growth and nourishment of
the baby in the womb and early life, explains Reik, where maternal and
paternal genomes are likely to be in conflict. The agenda of the father’s
genes is to produce a big, strong child most likely to survive and pass on
his genes, while the agenda of the mother’s genes is to constrain the growth
of the foetus to make birth easier and limit the demand on her during
pregnancy in the interests of any children she might have in the future.
This genetic interplay is exemplified in those born with Beckwith-Wiedemann
syndrome (BWS) – a disorder affecting about 1 in 15,000 babies,
characterised by high birth weight, an oversized tongue and risk of
childhood tumours. Such infants either have too much of a gene that promotes
cell growth, or too little of a gene to slow cell growth down. Reik and his
colleague Professor Eamonn Maher, a medical geneticist, started looking for
the cause of the syndrome about 15 years ago. They found that in 50% to 60%
of cases, the epigenetic “tags” were faulty. Their work also unearthed an
unsettling statistic. “One per cent of children born in the UK every year
are conceived by IVF,” says Maher. “However, we found that 4% of children
born with BWS had been conceived by IVF.” Within months of Reik and
Maher publishing their findings, American and French groups reported similar
trends. Although it is a concern, Maher is quick to clarify the figures.
“Because the syndrome is so rare to start off with, the absolute risk is
very small.” So what is it about the IVF process that might affect these
epigenetic tags? Animal studies have shown that epigenetic changes can occur
in embryos cultured in a Petri dish. Maher believes similar changes can
happen to human embryos too.
So epigenetics promises a great leap forward in understanding how we get ill.
But what about prevention and treatment? Hanson says: “If we really want to
change this epidemic of obesity, we’ve got to worry about health before
birth – and even before conception.” The biggest long-term gains, he
suggests, will come not from coaxing flabby adults into the gym but from
encouraging healthy habits at puberty.
Gluckman and Hanson have also looked at tinkering with the epigenetic process
itself to prevent disease. Last year they reported an experiment with rats
in which they injected newborns, programmed to convert calories efficiently
to fat, with a hormone that kidded their bodies they were fat enough. Fed on
a high-calorie diet, their litter mates quickly grew obese and developed
high blood pressure and diabetes, while the treated pups remained slim,
energetic and healthy. This was the first evidence that foetal programming
can be reversed or interfered with, and it made big waves in medical
literature.
Nobody is suggesting we give our children hormone injections at birth to stop
them turning into fat adults, but the idea that we may be able to reset our
biology for a better match with our environment is exciting. Reik is looking
for ways to remove epigenetic tags from DNA as a first step, and hopes to
find a way “to persuade cells to lose all their information and become stem
cells again that will work for us in therapy”.
None of this will translate into new practices in the clinic any day soon, but
cancer researchers are already working to develop drugs aimed at throwing
the epigenetic switches on genes that have been inappropriately silenced in
some forms of the disease, notably leukaemias. And Yehuda and others hope
epigenetic research will offer similar breakthroughs for psychiatry. At
present, she says, all that doctors can hope to do with the drugs available
is manage their patients’ symptoms, not offer a cure. But if epigenetics can
uncover at last the physical roots of the troubled mind, “it will
revolutionise the entire way we treat mental illness”
Additional reporting by Charlotte Hunt-Grubbe
Esther Waters and Megan Harrison
Both have Prader-Willi syndrome, a disorder characterised by a tendency to
obesity
Esther Waters is 28; Megan Harrison (below) is 8. Both suffer from PWS, caused
when genes in the father’s chromosome are silenced. Megan’s problems were
recognised soon after birth; Esther’s were not diagnosed until she began to
gain weight, aged 5, “for no apparent reason”, according to her mother,
Jackie.
“I had no idea what PWS was, and went hot and cold all over. All I could think
to ask the doctor was, ‘Will she grow up and get a job?’” Today, Esther is
on the trustees’ board of the day centre she attends and on the consultative
forum for people with disabilities with her local authority. She struggles
to keep her weight down. “We managed to keep her on a low-calorie diet until
she was about 15,” says Jackie. “But it’s got more difficult for her to
control her appetite as she’s got older, maybe partly because of the insulin
she’s on for her diabetes. But scientists are close to identifying the genes
on chromosome 15 responsible for PWS, and getting closer to what’s causing
the appetite problem.”
Early diagnosis meant that Megan’s family were able to anticipate problems as
she grew up and to help manage the voracious appetite and high risk of
obesity — hallmarks of PWS. Recent advances with growth hormones have helped
her physical development — today she enjoys horse-riding and is one of the
best swimmers in her class.
Sarah and Marcus Williams
The couple’s son, Ian, conceived through IVF, was born with
Beckwith-Wiedemann syndrome
Sarah and Marcus tried IVF three times before Ian, now 5, was conceived. The
Williamses also have a healthy daughter, Emily, 3, who was conceived
naturally. In 50-60% of cases, babies born with BWS have lost epigenetic
tags that control growth genes. The risk of having a child with BWS after
IVF rises from about 1 in 15,000 to 1 in 4,000.
“When I went for my 12-week scan,” Sarah explains, “the doctors said there was
something unusual about my child’s intestines — they were outside the body.
I was devastated. It was only at 16 weeks, when they told me Ian was bigger
than normal, that they asked me if I’d heard of BWS. I was told that all the
women who had come in with this so far had had terminations.
“At 22 weeks I had another scan, and we had a week to decide what to do. I
turned to an expert at St George’s hospital. She suggested we think about
keeping the baby — the children with BWS she’d seen were not as ill as had
been suggested. Ian was delivered by caesarean section. He was a big baby,
and as the doctors held him, my husband saw his intestines lying on his
stomach. They whisked him away to operate on him. Apart from his tongue
protruding, he appeared normal. The large tongue did cause problems. He
dribbled a lot and found it hard to feed. When he was three he had an
operation to reduce his tongue size and now he looks normal. The symptoms
were no way near as bad as we’d been led to expect. Now Ian is a happy
five-year-old, and as he grows up, the doctors tell us his slightly larger
size now should balance out later on. He is at school and loves it. Nobody
would realise he has a genetic difference at all. I would have had IVF again
to have Emily if it had been necessary, but luckily it wasn’t.”
