By Dan Hurley|Tuesday, June 11, 2013
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| Alison Mackey/DISCOVER |
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.
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Michael Meaney, neurobiologist.
Owen Egan/McGill University
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“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.
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Moshe Szyf, molecular biologist and geneticist.
McGill University
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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.
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 lays 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.
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| 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.”
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| 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.”
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| 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.
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| Alison Mackey/DISCOVER |
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.
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| Alison Mackey/DISCOVER |
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?
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