Grandma's Experiences Leave a Mark on Your Genes
Alison
Mackey/DISCOVER
Your ancestors' lousy
childhoods or excellent adventures might change your personality, bequeathing
anxiety or resilience by altering the epigenetic expressions of genes in the
brain.
By Dan Hurley
Darwin
and Freud walk into a bar. Two alcoholic mice — a mother and her son — sit on two
bar stools, lapping gin from two thimbles.
The
mother mouse looks up and says, “Hey, geniuses, tell me how my son got into
this sorry state.”
“Bad
inheritance,” says Darwin.
“Bad
mothering,” says Freud.
For
over a hundred years, those two views — nature or nurture, biology or
psychology — offered opposing explanations for how behaviors develop and
persist, not only within a single individual but across generations.
And
then, in 1992, two young scientists following in Freud’s and Darwin’s footsteps
actually did walk into a bar. And by the time they walked out, a few beers
later, they had begun to forge a revolutionary new synthesis of how life
experiences could directly affect your genes — and not only your own life
experiences, but those of your mother’s, grandmother’s and beyond.
The
bar was in Madrid, where
the Cajal Institute, Spain’s oldest academic center for the study of
neurobiology, was holding an international meeting. Moshe Szyf, a molecular
biologist and geneticist at McGill University in Montreal, had never studied
psychology or neurology, but he had been talked into attending by a colleague
who thought his work might have some application. Likewise, Michael Meaney, a
McGill neurobiologist, had been talked into attending by the same colleague,
who thought Meaney’s research into animal models of maternal neglect might
benefit from Szyf’s perspective.
Michael
Meaney, neurobiologist.
Owen
Egan/McGill University
“I
can still visualize the place — it was a corner bar that specialized in pizza,”
Meaney says. “Moshe, being kosher, was interested in kosher calories. Beer is
kosher. Moshe can drink beer anywhere. And I’m Irish. So it was perfect.”
The
two engaged in animated conversation about a hot new line of research in
genetics. Since the 1970s, researchers had known that the tightly wound spools
of DNA inside each cell’s nucleus require something extra to tell them exactly
which genes to transcribe, whether for a heart cell, a liver cell or a brain
cell.
One
such extra element is the methyl group, a common structural component of
organic molecules. The methyl group works like a placeholder in a cookbook,
attaching to the DNA within each cell to select only those recipes — er, genes
— necessary for that particular cell’s proteins. Because methyl groups are
attached to the genes, residing beside but separate from the double-helix DNA
code, the field was dubbed epigenetics, from the prefix epi (Greek for over,
outer, above).
Originally
these epigenetic changes were believed to occur only during fetal development.
But pioneering studies showed that molecular bric-a-brac could be added to DNA
in adulthood, setting off a cascade of cellular changes resulting in cancer.
Sometimes methyl groups attached to DNA thanks to changes in diet; other times,
exposure to certain chemicals appeared to be the cause. Szyf showed that
correcting epigenetic changes with drugs could cure certain cancers in
animals.
Geneticists
were especially surprised to find that epigenetic change could be passed down
from parent to child, one generation after the next. A study from Randy Jirtle
of Duke University showed that when female mice are fed a diet rich in methyl
groups, the fur pigment of subsequent offspring is permanently altered. Without
any change to DNA at all, methyl groups could be added or subtracted, and the
changes were inherited much like a mutation in a gene.
Moshe
Szyf, molecular biologist and geneticist.
McGill
University
Now,
at the bar in Madrid, Szyf and Meaney considered a hypothesis as improbable as
it was profound: If diet and chemicals can cause epigenetic changes, could
certain experiences — child neglect, drug abuse or other severe stresses — also
set off epigenetic changes to the DNA inside the neurons of a person’s brain?
That question turned out to be the basis of a new field, behavioral
epigenetics, now so vibrant it has spawned dozens of studies and suggested
profound new treatments to heal the brain.
According
to the new insights of behavioral epigenetics, traumatic experiences in our
past, or in our recent ancestors’ past, leave molecular scars adhering to our
DNA. Jews whose great-grandparents were chased from their Russian shtetls;
Chinese whose grandparents lived through the ravages of the Cultural
Revolution; young immigrants from Africa whose parents survived massacres; adults
of every ethnicity who grew up with alcoholic or abusive parents — all carry
with them more than just memories.
Like
silt deposited on the cogs of a finely tuned machine after the seawater of a
tsunami recedes, our experiences, and those of our forebears, are never gone,
even if they have been forgotten. They become a part of us, a molecular residue
holding fast to our genetic scaffolding. The DNA remains the same, but
psychological and behavioral tendencies are inherited. You might have inherited
not just your grandmother’s knobby knees, but also her predisposition toward
depression caused by the neglect she suffered as a newborn.
Or
not. If your grandmother was adopted by nurturing parents, you might be
enjoying the boost she received thanks to their love and support. The
mechanisms of behavioral epigenetics underlie not only deficits and weaknesses
but strengths and resiliencies, too. And for those unlucky enough to descend
from miserable or withholding grandparents, emerging drug treatments could
reset not just mood, but the epigenetic changes themselves. Like grandmother’s
vintage dress, you could wear it or have it altered. The genome has long been
known as the blueprint of life, but the epigenome is life’s Etch A Sketch:
Shake it hard enough, and you can wipe clean the family curse.
Jay
Smith/DISCOVER
Voodoo Genetics
Twenty
years after helping to set off a revolution, Meaney sits behind a wide walnut table that
serves as his desk. A January storm has deposited half a foot of snow outside
the picture windows lining his fourth-floor corner office at the Douglas
Institute, a mental health affiliate of McGill. He has the rugged good looks
and tousled salt-and-pepper hair of someone found on a ski slope — precisely
where he plans to go this weekend. On the floor lies an arrangement of helium
balloons in various stages of deflation. “Happy 60th!” one announces.
“I’ve
always been interested in what makes people different from each other,” he
says. “The way we act, the way we behave — some people are optimistic, some are
pessimistic. What produces that variation? Evolution selects the variance that
is most successful, but what produces the grist for the mill?”
Meaney
pursued the question of individual differences by studying how the rearing
habits of mother rats caused lifelong changes in their offspring. Research
dating back to the 1950s had shown that rats handled by humans for as little as
five to 15 minutes per day during their first three weeks of life grew up to be
calmer and less reactive to stressful environments compared with their
non-handled littermates. Seeking to tease out the mechanism behind such an
enduring effect, Meaney and others established that the benefit was not
actually conveyed by the human handling. Rather, the handling simply provoked
the rats’ mothers to lick and groom their pups more, and to engage more often
in a behavior called arched-back nursing, in which the mother gives the pups
extra room to suckle against her underside.
“It’s
all about the tactile stimulation,” Meaney says.
In
a landmark 1997 paper in Science,
he showed that natural variations in the amount of licking and grooming
received during infancy had a direct effect on how stress hormones, including
corticosterone, were expressed in adulthood. The more licking as babies, the
lower the stress hormones as grown-ups. It was almost as if the mother rats
were licking away at a genetic dimmer switch. What the paper didn’t explain was
how such a thing could be possible.
"What
we had done up to that point in time was to identify maternal care and its
influence on specific genes,” Meaney says. “But epigenetics wasn’t a topic I
knew very much about.”
And
then he met Szyf.
Alison
Mackey/DISCOVER
Postnatal Inheritance
“I
was going to be a dentist,” Szyf says with a laugh. Slight, pale and
balding, he sits in a small office at the back of his bustling laboratory — a
room so Spartan, it contains just a single picture, a photograph of two embryos
in a womb.
Needing
to write a thesis in the late 1970s for his doctorate in dentistry at Hebrew
University of Jerusalem, Szyf approached a young biochemistry professor named
Aharon Razin, who had recently made a splash by publishing his first few
studies in some of the world’s top scientific journals. The studies were the
first to show that the action of genes could be modulated by structures called
methyl groups, a subject about which Szyf knew precisely nothing. But he needed
a thesis adviser, and Razin was there. Szyf found himself swept up to the
forefront of the hot new field of epigenetics and never looked back.
Until
researchers like Razin came along, the basic story line on how genes get
transcribed in a cell was neat and simple. DNA is the master code, residing
inside the nucleus of every cell; RNA transcribes the code to build whatever
proteins the cell needs. Then some of Razin’s colleagues showed that methyl
groups could attach to cytosine, one of the chemical bases in DNA and RNA.
It
was Razin, working with fellow biochemist Howard Cedar, who showed these
attachments weren’t just brief, meaningless affairs. The methyl groups could
become married permanently to the DNA, getting replicated right along with it
through a hundred generations. As in any good marriage, moreover, the
attachment of the methyl groups significantly altered the behavior of whichever
gene they wed, inhibiting its transcription, much like a jealous spouse. It did
so, Razin and Cedar showed, by tightening the thread of DNA as it wrapped
around a molecular spool, called a histone, inside the nucleus. The tighter it
is wrapped, the harder to produce proteins from the gene.
Consider
what that means: Without a mutation to the DNA code itself, the attached methyl
groups cause long-term, heritable change in gene function. Other molecules,
called acetyl groups, were found to play the opposite role, unwinding DNA
around the histone spool, and so making it easier for RNA to transcribe a given
gene.
By
the time Szyf arrived at McGill in the late 1980s, he had become an expert in
the mechanics of epigenetic change. But until meeting Meaney, he had never
heard anyone suggest that such changes could occur in the brain, simply due to
maternal care.
“It
sounded like voodoo at first,” Szyf admits. “For a molecular biologist,
anything that didn’t have a clear molecular pathway was not serious science.
But the longer we talked, the more I realized that maternal care just might be
capable of causing changes in DNA methylation, as crazy as that sounded. So
Michael and I decided we’d have to do the experiment to find out.”
Thinkstock
Actually,
they ended up doing a series of elaborate experiments. With the assistance of
postdoctoral researchers, they began by selecting mother rats who were either
highly attentive or highly inattentive. Once a pup had grown up into adulthood,
the team examined its hippocampus, a brain region essential for regulating the
stress response. In the pups of inattentive mothers, they found that genes
regulating the production of glucocorticoid receptors, which regulate
sensitivity to stress hormones, were highly methylated; in the pups of
conscientious moms, the genes for the glucocorticoid receptors were rarely
methylated.
Methylation
just gums up the works. So the less the better when it comes to transcribing
the affected gene. In this case, methylation associated with miserable
mothering prevented the normal number of glucocorticoid receptors from being
transcribed in the baby’s hippocampus. And so for want of sufficient
glucocorticoid receptors, the rats grew up to be nervous wrecks.
To
demonstrate that the effects were purely due to the mother’s behavior and not
her genes, Meaney and colleagues performed a second experiment. They took rat
pups born to inattentive mothers and gave them to attentive ones, and vice
versa. As they predicted, the rats born to attentive mothers but raised by
inattentive ones grew up to have low levels of glucocorticoid receptors in
their hippocampus and behaved skittishly. Likewise, those born to bad mothers
but raised by good ones grew up to be calm and brave and had high levels of
glucocorticoid receptors.
Before
publishing their findings, Meaney and Szyf conducted a third crucial
experiment, hoping to overwhelm the inevitable skeptics who would rise up to
question their results. After all, it could be argued, what if the epigenetic
changes observed in the rats’ brains were not directly causing the behavioral
changes in the adults, but were merely co-occurring? Freud certainly knew the
enduring power of bad mothers to screw up people’s lives. Maybe the emotional
effects were unrelated to the epigenetic change.
To
test that possibility, Meaney and Szyf took yet another litter of rats raised
by rotten mothers. This time, after the usual damage had been done, they
infused their brains with trichostatin A, a drug that can remove methyl groups.
These animals showed none of the behavioral deficits usually seen in such
offspring, and their brains showed none of the epigenetic changes.
“It
was crazy to think that injecting it straight into the brain would work,” says
Szyf. “But it did. It was like rebooting a computer.”
Jay
Smith/DISCOVER
Despite
such seemingly overwhelming evidence, when the pair wrote it all up in a paper,
one of the reviewers at a top science journal refused to believe it, stating he
had never before seen evidence that a mother’s behavior could cause epigenetic
change.
“Of
course he hadn’t,” Szyf says. “We wouldn’t have bothered to report the study if
it had already been proved.”
In
the end, their landmark paper, “Epigenetic programming by maternal behavior,”
was published in June 2004 in the journal Nature
Neuroscience.
Meaney
and Szyf had proved something incredible. Call it postnatal inheritance: With
no changes to their genetic code, the baby rats nonetheless gained genetic
attachments due solely to their upbringing — epigenetic
additions of methyl groups sticking like umbrellas out the elevator doors of
their histones, gumming up the works and altering the function of the brain.
The Beat Goes On
Together,
Meaney and Szyf have gone on to publish some two-dozen papers, finding evidence
along the way of epigenetic changes to many other genes active in the brain.
Perhaps most significantly, in a study led by Frances Champagne — then a
graduate student in Meaney’s lab, now an associate professor with her own lab
at Columbia University in New York — they found that inattentive mothering in
rodents causes methylation of the genes for estrogen receptors in the brain.
When those babies grow up, the resulting decrease of estrogen receptors makes
them less attentive to their
babies. And so the beat goes on.
As
animal experiments continue apace, Szyf and Meaney have entered into the next
great step in the study of behavioral epigenetics: human studies. In a 2008
paper, they compared the brains of people who had committed suicide with the
brains of people who had died suddenly of factors other than suicide. They
found excess methylation of genes in the suicide brains’ hippocampus, a region
critical to memory acquisition and stress response. If the suicide victims had
been abused as children, they found, their brains were more methylated.
Why
can’t your friend “just get over” her upbringing by an angry, distant mother?
Why can’t she “just snap out of it”? The reason may well be due to methyl
groups that were added in childhood to genes in her brain, thereby handcuffing
her mood to feelings of fear and despair.
Of
course, it is generally not possible to sample the brains of living people. But
examining blood samples in humans is routine, and Szyf has gone searching there
for markers of epigenetic methylation. Sure enough, in 2011 he reported on a
genome-wide analysis of blood samples taken from 40 men who participated in a
British study of people born in England in 1958.
All
the men had been at a socioeconomic extreme, either very rich or very poor, at
some point in their lives ranging from early childhood to mid-adulthood. In
all, Szyf analyzed the methylation state of about 20,000 genes. Of these, 6,176
genes varied significantly based on poverty or wealth. Most striking, however,
was the finding that genes were more than twice as likely to show methylation
changes based on family income during early childhood versus economic status as
adults.
Timing,
in other words, matters. Your parents winning the lottery or going bankrupt
when you’re 2 years old will likely affect the epigenome of your brain, and
your resulting emotional tendencies, far more strongly than whatever fortune
finds you in middle age.
Last
year, Szyf and researchers from Yale University published another study of
human blood samples, comparing 14 children raised in Russian orphanages with 14
other Russian children raised by their biological parents. They found far more
methylation in the orphans’ genes, including many that play an important role
in neural communication and brain development and function.
“Our
study shows that the early stress of separation from a biological parent
impacts long-term programming of genome function; this might explain why
adopted children may be particularly vulnerable to harsh parenting in terms of
their physical and mental health,” said Szyf’s co-author, psychologist Elena
Grigorenko of the Child Study Center at Yale. “Parenting adopted children might
require much more nurturing care to reverse these changes in genome
regulation.”
A
case study in the epigenetic effects of upbringing in humans can be seen in the
life of Szyf’s and Meaney’s onetime collaborator, Frances Champagne. “My mom
studied prolactin, a hormone involved in maternal behavior. She was a driving
force in encouraging me to go into science,” she recalls. Now a leading figure
in the study of maternal influence, Champagne just had her first child, a
daughter. And epigenetic research has taught her something not found in the What to Expect books or
even her mother’s former lab.
“The
thing I’ve gained from the work I do is that stress is a big suppressor of
maternal behavior,” she says. “We see it in the animal studies, and it’s true
in humans. So the best thing you can do is not to worry all the time about
whether you’re doing the right thing. Keeping the stress level down is the most
important thing. And tactile interaction — that’s certainly what the good
mother rats are doing with their babies. That sensory input, the touching, is
so important for the developing brain.”
The Mark Of Cain
The
message that a mother’s love can make all the difference in a child’s life is
nothing new.
But the ability of epigenetic change to persist across generations remains the
subject of debate. Is methylation transmitted directly through the fertilized
egg, or is each infant born pure, a methylated virgin, with the attachments of
methyl groups slathered on solely by parents after birth?
Neuroscientist
Eric Nestler of the Icahn School of Medicine at Mount Sinai in New York has
been seeking an answer for years. In one study, he exposed male mice to 10 days
of bullying by larger, more aggressive mice. At the end of the experiment, the
bullied mice were socially withdrawn.
To
test whether such effects could be transmitted to the next generation, Nestler
took another group of bullied mice and bred them with females, but kept them
from ever meeting their offspring.
Despite
having no contact with their depressed fathers, the offspring grew up to be
hypersensitive to stress. “It was not a subtle effect; the offspring were
dramatically more susceptible to developing signs of depression,” he says.
In
further testing, Nestler took sperm from defeated males and impregnated females
through in vitro fertilization. The offspring did not show most of the
behavioral abnormalities, suggesting that epigenetic transmission may not be at
the root. Instead, Nestler proposes, “the female might know she had sex with a
loser. She knows it’s a tainted male she had sex with, so she cares for her
pups differently,” accounting for the results.
Despite
his findings, no consensus has yet emerged. The latest evidence, published in
the Jan. 25 issue of the journal Science,
suggests that epigenetic changes in mice are usually erased, but not always.
The erasure is imperfect, and sometimes the affected genes may make it through
to the next generation, setting the stage for transmission of the altered
traits in descendants as well.
What’s Next?
The
studies keep piling on. One line of research traces memory loss in old age to
epigenetic alterations in brain neurons. Another connects post-traumatic stress
disorder to methylation of the gene coding for neurotrophic factor, a protein
that regulates the growth of neurons in the brain.
If
it is true that epigenetic changes to genes active in certain regions of the
brain underlie our emotional and intellectual intelligence — our tendency to be
calm or fearful, our ability to learn or to forget — then the question arises:
Why can’t we just take a drug to rinse away the unwanted methyl groups like a
bar of epigenetic Irish Spring?
The
hunt is on. Giant pharmaceutical and smaller biotech firms are searching for
epigenetic compounds to boost learning and memory. It has been lost on no one
that epigenetic medications might succeed in treating depression, anxiety and
post-traumatic stress disorder where today’s psychiatric drugs have
failed.
But
it is going to be a leap. How could we be sure that epigenetic drugs would
scrub clean only the dangerous marks, leaving beneficial — perhaps essential —
methyl groups intact? And what if we could create a pill potent enough to wipe
clean the epigenetic slate of all that history wrote? If such a pill could free
the genes within your brain of the epigenetic detritus left by all the wars,
the rapes, the abandonments and cheated childhoods of your ancestors, would you
take it?
[This
article originally appeared in print as "Trait vs. Fate"]
From Discover Magazine
@ http://discovermagazine.com/2013/may/13-grandmas-experiences-leave-epigenetic-mark-on-your-genes
For more information about epigenetics see http://nexusilluminati.blogspot.com/search/label/epigenetics
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