Is Not Destiny
The new science of epigenetics rewrites the rules of
disease, heredity, and identity.
By Ethan Watters
DISCOVER Vol. 27 No. 11 | November 2006 | Medicine
Back in 2000, Randy Jirtle, a professor of radiation
oncology at Duke University, and his postdoctoral student
Robert Waterland designed a groundbreaking genetic
experiment that was simplicity itself. They started
with pairs of fat yellow mice known to scientists as
agouti mice, so called because they carry a particular
gene—the agouti gene—that in addition to
making the rodents ravenous and yellow renders them
prone to cancer and diabetes. Jirtle and Waterland
set about to see if they could change the unfortunate
genetic legacy of these little creatures.
Typically, when agouti mice breed, most of the offspring
are identical to the parents: just as yellow, fat as
pincushions, and susceptible to life-shortening disease.
The parent mice in Jirtle and Waterland's experiment,
however, produced a majority of offspring that looked
altogether different. These young mice were slender
and mousy brown. Moreover, they did not display their
parents' susceptibility to cancer and diabetes and
lived to a spry old age. The effects of the agouti
gene had been virtually erased.
the researchers effected this transformation without
altering a single letter of the mouse's DNA.
Their approach instead was radically straightforward—they
changed the moms' diet. Starting just before conception,
Jirtle and Waterland fed a test group of mother mice
a diet rich in methyl donors, small chemical clusters
that can attach to a gene and turn it off. These molecules
are common in the environment and are found in many
foods, including onions, garlic, beets, and in the
food supplements often given to pregnant women. After
being consumed by the mothers, the methyl donors worked
their way into the developing embryos' chromosomes
and onto the critical agouti gene. The mothers passed
along the agouti gene to their children intact, but
thanks to their methyl-rich pregnancy diet, they had
added to the gene a chemical switch that dimmed the
gene's deleterious effects.
was a little eerie and a little scary to see how something
as subtle as a nutritional change in the pregnant mother
rat could have such a dramatic impact on the gene expression
of the baby," Jirtle says. "The results showed
how important epigenetic changes could be."
DNA—specifically the 25,000 genes identified
by the Human Genome Project—is now widely regarded
as the instruction book for the human body. But genes
themselves need instructions for what to do, and
where and when to do it. A human liver cell contains
same DNA as a brain cell, yet somehow it knows to
code only those proteins needed for the functioning
liver. Those instructions are found not in the letters
of the DNA itself but on it, in an array of chemical
markers and switches, known collectively as the epigenome,
that lie along the length of the double helix. These
epigenetic switches and markers in turn help switch
on or off the expression of particular genes. Think
of the epigenome as a complex software code, capable
of inducing the DNA hardware to manufacture an impressive
variety of proteins, cell types, and individuals.
recent years, epigenetics researchers have made great
strides in understanding the many molecular sequences
and patterns that determine which genes can be turned
on and off. Their work has made it increasingly clear
that for all the popular attention devoted to genome-sequencing
projects, the epigenome is just as critical as DNA
to the healthy development of organisms, humans included.
Jirtle and Waterland's experiment was a benchmark demonstration
that the epigenome is sensitive to cues from the environment.
More and more, researchers are finding that an extra
bit of a vitamin, a brief exposure to a toxin, even
an added dose of mothering can tweak the epigenome—and
thereby alter the software of our genes—in ways
that affect an individual's body and brain for life.
The even greater surprise is the recent discovery
that epigenetic signals from the environment can be
passed on from one generation to the next, sometimes
for several generations, without changing a single
gene sequence. It's well established, of course, that
environmental effects like radiation, which alter the
genetic sequences in a sex cell's DNA, can leave a
mark on subsequent generations. Likewise, it's known
that the environment in a mother's womb can alter the
development of a fetus. What's eye-opening is a growing
body of evidence suggesting that the epigenetic changes
wrought by one's diet, behavior, or surroundings can
work their way into the germ line and echo far into
the future. Put simply, and as bizarre as it may sound,
what you eat or smoke today could affect the health
and behavior of your great-grandchildren.
All of these
discoveries are shaking the modern biological and
social certainties about genetics and identity.
We commonly accept the notion that through our DNA
we are destined to have particular body shapes, personalities,
and diseases. Some scholars even contend that the genetic
code predetermines intelligence and is the root cause
of many social ills, including poverty, crime, and
violence. "Gene as fate" has become conventional
wisdom. Through the study of epigenetics, that notion
at last may be proved outdated. Suddenly, for better
or worse, we appear to have a measure of control over
our genetic legacy.
"Epigenetics is proving we have some responsibility
for the integrity of our genome," Jirtle says. "Before,
genes predetermined outcomes. Now everything we do—everything
we eat or smoke—can affect our gene expression
and that of future generations. Epigenetics introduces
the concept of free will into our idea of genetics."
are still coming to understand the many ways that
epigenetic changes unfold at the biochemical
level. One form of epigenetic change physically blocks
access to the genes by altering what is called the
histone code. The DNA in every cell is tightly wound
around proteins known as histones and must be unwound
to be transcribed. Alterations to this packaging cause
certain genes to be more or less available to the cell's
chemical machinery and so determine whether those genes
are expressed or silenced. A second, well-understood
form of epigenetic signaling, called DNA methylation,
involves the addition of a methyl group—a carbon
atom plus three hydrogen atoms—to particular
bases in the DNA sequence. This interferes with the
chemical signals that would put the gene into action
and thus effectively silences the gene.
Until recently, the pattern of an individual's epigenome
was thought to be firmly established during early fetal
development. Although that is still seen as a critical
period, scientists have lately discovered that the
epigenome can change in response to the environment
throughout an individual's lifetime.
"People used to think that once your epigenetic
code was laid down in early development, that was it
for life," says Moshe Szyf, a pharmacologist with
a bustling lab at McGill University in Montreal. "But
life is changing all the time, and the epigenetic
code that controls your DNA is turning out to be
through which we change along with it. Epigenetics
tells us that little things in life can have an effect
of great magnitude."
has been a pioneer in linking epigenetic changes
development of diseases. He long ago championed
the idea that epigenetic patterns can shift through
life and that those changes are important in the establishment
and spread of cancer. For 15 years, however, he had
little luck convincing his colleagues. One of his papers
was dismissed by a reviewer as a "misguided attempt
at scientific humor." On another occasion, a prominent
scientist took him aside and told him bluntly, "Let
me be clear: Cancer is genetic in origin, not epigenetic."
such opposition, Szyf and other researchers have
persevered. Through numerous studies, Szyf has
found that common signaling pathways known to lead
to cancerous tumors also activate the DNA-methylation
machinery; knocking out one of the enzymes in that
pathway prevents the tumors from developing. When genes
that typically act to suppress tumors are methylated,
the tumors metastasize. Likewise, when genes that typically
promote tumor growth are demethylated—that is,
the dimmer switches that are normally present are removed—those
genes kick into action and cause tumors to grow.
Szyf is now far from alone in the field. Other researchers
have identified dozens of genes, all related to the
growth and spread of cancer, that become over- or undermethylated
when the disease gets under way. The bacteria Helicobacter,
believed to be a cause of stomach cancer, has been
shown to trigger potentially cancer-inducing epigenetic
changes in gut cells. Abnormal methylation patterns
have been found in many cancers of the colon, stomach,
cervix, prostate, thyroid, and breast.
Szyf views the link between epigenetics and cancer
with a hopeful eye. Unlike genetic mutations,
epigenetic changes are potentially reversible. A mutated
gene is unlikely to mutate back to normal; the only
is to kill or cut out all the cells carrying the defective
code. But a gene with a defective methylation pattern
might very well be encouraged to reestablish a healthy
pattern and continue to function. Already one epigenetic
drug, 5-azacytidine, has been approved by the Food
and Drug Administration for use against myelodysplastic
syndrome, also known as preleukemia or smoldering leukemia.
At least eight other epigenetic drugs are currently
in different stages of development or human trials.
Methylation patterns also hold promise as diagnostic
tools, potentially yielding critical information about
the odds that a cancer will respond to treatment. A
Berlin-based company called Epigenomics, in partnership
with Roche Pharmaceuticals, expects to bring an epigenetic
screening test for colon cancer to market by 2008.
They are working on similar diagnostic tools for breast
cancer and prostate cancer. Szyf has cofounded a company,
MethylGene, that so far has developed two epigenetic
cancer drugs with promising results in human trials.
Others have published data on animal subjects suggesting
an epigenetic component to inflammatory diseases like
rheumatoid arthritis, neurodegenerative diseases, and
researchers are focusing on how people might maintain
of their epigenomes through
diet. Baylor College of Medicine obstetrician and geneticist
Ignatia Van den Veyver suggests that once we understand
the connection between our epigenome and diseases like
cancer, lifelong "methylation diets" may
be the trick to staying healthy. Such diets, she says,
could be tailored to an individual's genetic makeup,
as well as to their exposure to toxins or cancer-causing
In 2003 biologist Ming Zhu Fang and her colleagues
at Rutgers University published a paper in the journal
Cancer Research on the epigenetic effects of green
tea. In animal studies, green tea prevented
the growth of cancers in several organs. Fang found that epigallocatechin-3-gallate
(EGCG), the major polyphenol from green tea, can prevent
deleterious methylation dimmer switches from landing
on (and shutting down) certain cancer-fighting genes.
The researchers described the study as the first to
demonstrate that a consumer product can inhibit DNA
methylation. Fang and her colleagues have since gone
on to show that genistein and other compounds in soy
show similar epigenetic effects.
epigenetic researchers around the globe are rallying
behind the idea of a human epigenome project,
which would aim to map our entire epigenome. The Human
Genome Project, which sequenced the 3 billion pairs
of nucleotide bases in human DNA, was a piece of cake
in comparison: Epigenetic markers and patterns are
different in every tissue type in the human body and
also change over time. "The epigenome project
is much more difficult than the Human Genome Project," Jirtle
says. "A single individual doesn't have one epigenome
but a multitude of them."
Research centers in Japan, Europe, and the United
States have all begun individual pilot studies to assess
the difficulty of such a project. The early signs are
encouraging. In June, the European Human Epigenome
Project released its data on epigenetic patterns of
three human chromosomes. A recent flurry of conferences
have forwarded the idea of creating an international
epigenome project that could centralize the data, set
goals for different groups, and standardize the technology
for decoding epigenetic patterns.
recently, the idea that your environment might change
heredity without changing a gene sequence
was scientific heresy. Everyday influences—the
weights Dad lifts to make himself muscle-bound, the
diet regimen Mom follows to lose pounds—don't
produce stronger or slimmer progeny, because those
changes don't affect the germ cells involved in making
children. Even after the principles of epigenetics
came to light, it was believed that methylation marks
and other epigenetic changes to a parent's DNA were
lost during the process of cell division that generates
eggs and sperm and that only the gene sequence remained.
In effect, it was thought, germ cells wiped the slate
clean for the next generation.
That turns out not to be the case. In 1999 biologist
Emma Whitelaw, now at the Queensland Institute of Medical
Research in Australia, demonstrated that epigenetic
marks could be passed from one generation of mammals
to the next. (The phenomenon had already been demonstrated
in plants and yeast.) Like Jirtle and Waterland in
2003, Whitelaw focused on the agouti gene in mice,
but the implications of her experiment span the animal
"It changes the way we think about information
transfer across generations," Whitelaw says. "The
mind-set at the moment is that the information we inherit
from our parents is in the form of DNA. Our experiment
demonstrates that it's more than just DNA you inherit.
In a sense that's obvious, because what we inherit
from our parents are chromosomes, and chromosomes are
only 50 percent DNA. The other 50 percent is made up
of protein molecules, and these proteins carry the
epigenetic marks and information."
Meaney, a biologist at McGill University and a frequent
collaborator with Szyf, has pursued an equally provocative
notion: that some epigenetic changes can
be induced after birth, through a mother's physical behavior
toward her newborn. For years, Meaney sought to explain
some curious results he had observed involving the
nurturing behavior of rats. Working with graduate
student Ian Weaver, Meaney compared two types of
mother rats: those that patiently licked their offspring
after birth and those that neglected their newborns.
The licked newborns grew up to be relatively brave
and calm (for rats). The neglected newborns grew
into the sort of rodents that nervously skitter into
the darkest corner when placed in a new environment.
researchers might have offered an explanation on
one side or the other of the nature-versus-nurture
divide. Either the newborns inherited a genetic propensity
to be skittish or brave (nature), or they were learning
the behavior from their mothers (nurture). Meaney
and Weaver's results didn't fall neatly into either
camp. After analyzing the brain tissue of both licked
and nonlicked rats, the researchers found distinct
differences in the DNA methylation patterns in the
hippocampus cells of each group. Remarkably, the
mother's licking activity had the effect of removing
dimmer switches on a gene that shapes stress receptors
in the pup's growing brain. The well-licked rats
had better-developed hippocampi and released less
of the stress hormone cortisol, making them calmer
when startled. In contrast, the neglected pups released
much more cortisol, had less-developed hippocampi,
and reacted nervously when startled or in new surroundings.
Through a simple maternal behavior, these mother
rats were literally shaping the brains of their offspring.
exactly does the mother's behavior cause the epigenetic
change in her pup? Licking and grooming release serotonin
in the pup's brain, which activates serotonin receptors
in the hippocampus. These receptors send proteins
called transcription factors to turn on the gene
that inhibits stress responses. Meaney, Weaver, and
Szyf think that the transcription factors, which
normally regulate genes in passing, also carry methylation
machinery that can alter gene expression permanently.
In two subsequent studies, Meaney and his colleagues
were even able to reverse the epigenetic signals
by injecting the drug trichostatin A into the brains
of adult rats. In effect, they were able to simulate
the effect of good (and bad) parenting with a pharmaceutical
intervention. Trichostatin, interestingly, is chemically
similar to the drug valproate, which is used clinically
in people as a mood stabilizer.
says the link between nurturing and brain development
is more than just a curious cause and effect. He
suggests that making postnatal changes to an offspring's
epigenome offers an adaptive advantage. Through such
tweaking, mother rats have a last chance to mold
their progeny to suit the environment they were born
into. "These experiments emphasize the importance
of context on the development of a creature," Meaney
says. "They challenge the overriding theories
of both biology and psychology. Rudimentary adaptive
responses are not innate or passively emerging from
the genome but are molded by the environment."
hippocampus in a sheep's brain. Meany's research
showed that, in rats, hippocampus size is influenced
by maternal nurturing behavior such as licking after
birth. Well-licked rats had more developed hippocampi
and produced less of the stress hormone corstisol.
(Courtesy of the University of Pennsylvania School
of Veterinary Medicine)
now aims to see whether similar epigenetic changes
occur when human mothers caress and hold their infants.
He notes that the genetic sequence silenced by attentive
mother rats has a close parallel in the human genome,
so he expects to find a similar epigenetic influence. "It's
just not going to make any sense if we don't find
this in humans as well. The story is going to be
more complex than with the rats because we'll have
to take into account more social influences, but
I'm convinced we're going to find a connection."
an early study, which provided circumstantial evidence,
Meaney examined magnetic resonance imaging brain
scans of adults who began life as low-birth-weight
babies. Those adults who reported in a questionnaire
that they had a poor relationship with their mother
were found to have hippocampi that were significantly
smaller than average. Those adults who reported having
had a close relationship with their mother, however,
showed perfectly normal size hippocampi. Meaney acknowledges
the unreliability of subjects reporting on their
own parental relationships; nonetheless, he strongly
suspects that the quality of parenting was responsible
for the different shapes of the brains of these two
an effort to solidify the connection, he and other
researchers have launched an ambitious five-year
multimillion-dollar study to examine the effects
of early nurturing on hundreds of human babies. As
a test group, he's using severely depressed mothers
who often have difficulty bonding and caring for
their newborns and, as a result, tend to caress their
babies less than mothers who don't experience depression
or anxiety. The question is whether the babies of
depressed mothers show the distinct brain shapes
and patterns indicative of epigenetic differences.
science of epigenetics opens a window onto the inner
workings of many human diseases. It also raises some
provocative new questions. Even as we consider manipulating
the human epigenome to benefit our health, some researchers
are concerned that we may already be altering our
epigenomes unintentionally, and perhaps not for the
better. Jirtle notes that the prenatal vitamins that
physicians commonly encourage pregnant women to take
to reduce the incidence of birth defects in their
infants include some of the same chemicals that Jirtle
fed to his agouti mice. In effect, Jirtle wonders
whether his mouse experiment is being carried out
wholesale on American women.
top of the prenatal vitamins, every bit of grain
product that we eat in the country is now fortified
with folic acid," Jirtle notes, and folic acid
is a known methyl donor. "In addition, some
women take multivitamins that also have these compounds.
They're getting a triple hit."
the prenatal supplements have an undisputed positive
effect, Jirtle says, no one knows where else in the
fetal genome those gene-silencing methyl donors might
be landing. A methyl tag that has a positive effect
on one gene might have a deleterious effect if it
happens to fall somewhere else. "It's the American
way to think, 'If a little is good, a lot is great.'
But that is not necessarily the case here. You might
be overmethylating certain genes, which could potentially
cause other things like autism and other negative
shares the concern. "Fueling the methylation
machinery through dietary supplements is a dangerous
experiment, because there is likely to be a plethora
of effects throughout a lifetime." In the future,
he believes, epidemiologists will have their hands
full looking for possible epigenetic consequences
of these public-health choices. "Did this change
in diet increase cancer risk? Did it increase depression?
Did it increase schizophrenia? Did it increase dementia
or Alzheimer's? We don't know yet. And it will take
some time to sort it out."
of the epigenetic revolution are even more profound
in light of recent evidence that
epigenetic changes made in the parent generation can
turn up not just one but several generations down the
line, long after the original trigger for change has
been removed. In 2004 Michael Skinner, a geneticist
at Washington State University, accidentally discovered
an epigenetic effect in rats that lasts at least four
generations. Skinner was studying how a commonly used
agricultural fungicide, when introduced to pregnant
mother rats, affected the development of the testes
of fetal rats. He was not surprised to discover that
male rats exposed to high doses of the chemical while
in utero had lower sperm counts later in life. The
surprise came when he tested the male rats in subsequent
generations—the grandsons of the exposed mothers.
Although the pesticide had not changed one letter of
their DNA, these second-generation offspring also had
low sperm counts. The same was true of the next generation
(the great-grandsons) and the next.
Such results hint at a seemingly anti-Darwinian aspect
of heredity. Through epigenetic alterations, our genomes
retain something like a memory of the environmental
signals received during the lifetimes of our parents,
grandparents, great-grandparents, and perhaps even
more distant ancestors. So far, the definitive studies
have involved only rodents. But researchers are turning
up evidence suggesting that epigenetic inheritance
may be at work in humans as well.
2005, Marcus Pembrey, a clinical geneticist at the
Institute of Child Health in London, attended
a conference at Duke University to present intriguing
data drawn from two centuries of records on crop yields
and food prices in an isolated town in northern Sweden.
Pembrey and Swedish researcher Lars Olov Bygren noted
that fluctuations in the towns' food supply may have
health effects spanning at least two generations. Grandfathers
who lived their preteen years during times of plenty
were more likely to have grandsons with diabetes—an
ailment that doubled the grandsons' risk of early death.
Equally notable was that the effects were sex specific.
A grandfather's access to a plentiful food supply affected
the mortality rates of his grandsons only, not those
of his granddaughters, and a paternal grandmother's
experience of feast affected the mortality rates of
her granddaughters, not her grandsons.
Pembrey to suspect that genes on the sex-specific
X and Y chromosomes were being affected by epigenetic
signals. Further analysis supported his hunch and offered
insight into the signaling process. It turned out that
timing—the ages at which grandmothers and grandfathers
experienced a food surplus—was critical to the
intergenerational impact. The granddaughters most affected
were those whose grandmothers experienced times of
plenty while in utero or as infants, precisely the
time when the grandmothers' eggs were forming. The
grandsons most affected were those whose grandfathers
experienced plenitude during the so-called slow growth
period, just before adolescence, which is a key stage
for the development of sperm.
by Pembrey and other epigenetics researchers suggest
that our diet, behavior, and environmental
surroundings today could have a far greater impact
than imagined on the health of our distant descendants. "Our
study has shown a new area of research that could potentially
make a major contribution to public health and have
a big impact on the way we view our responsibilities
toward future generations," Pembrey says.
The logic applies backward as well as forward: Some
of the disease patterns prevalent today may have deep
epigenetic roots. Pembrey and several other researchers,
for instance, have wondered whether the current epidemic
of obesity, commonly blamed on the excesses of the
current generation, may partially reflect lifestyles
adopted by our forebears two or more generations back.
Michael Meaney, who studies the impact of nurturing,
likewise wonders what the implications of epigenetics
are for social policy. He notes that early child-parent
bonding is made more difficult by the effects of poverty,
dislocation, and social strife. Those factors can certainly
affect the cognitive development of the children directly
involved. Might they also affect the development of
future generations through epigenetic signaling?
"These ideas are likely to have profound consequences
when you start to talk about how the structure of society
influences cognitive development," Meaney says. "We're
beginning to draw cause-and-effect arrows between social
and economic macrovariables down to the level of the
child's brain. That connection is potentially quite
Harper, a psychologist at the University of California
at Davis, suggests that a wide array
of personality traits, including temperament and intelligence,
may be affected by epigenetic inheritance. "If
you have a generation of poor people who suffer from
bad nutrition, it may take two or three generations
for that population to recover from that hardship and
reach its full potential," Harper says. "Because
of epigenetic inheritance, it may take several generations
to turn around the impact of poverty or war or dislocation
on a population."
genetics has not meshed well with discussions of
social policy; it's all too easy to view disadvantaged
groups—criminals, the poor, the ethnically marginalized—as
somehow fated by DNA to their condition. The advent
of epigenetics offers a new twist and perhaps an opportunity
to understand with more nuance how nature and nurture
combine to shape the society we live in today and hope
to live in tomorrow.
"Epigenetics will have a dramatic impact on how
we understand history, sociology, and political science," says
Szyf. "If environment has a role to play in changing
your genome, then we've bridged the gap between social
processes and biological processes. That will change
the way we look at everything."