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Ukazujem Revíziu 5 vytvorenú 10/25/2017 od DLC.

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    We are on the brink of uncovering
    a hidden world, a world that
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    connects past and future generations
    in ways we never thought possible.
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    What this means is that an environmental
    exposure that your grandmother had
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    could cause a disease in you, even though
    have never been exposed to the toxin,
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    and you are going to pass it on to your
    great-grandkids.
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    These extraordinary discoveries have the
    to effect every aspect of our lives.
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    It's not just the genes, but also the
    environment of the early life
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    of your early ancestors. It's not so much
    you are what you eat, but you are what
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    your mother ate, and maybe you are what
    your grandmother ate. And if you take our
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    data, maybe you are what your grandmother
    or grandfather had.
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    It will change the way we think about our
    relationship with every generation.
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    Makes me feel closer to my children;
    what I experienced in terms of environment
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    will have some type of legacy in my
    children and grandchildren.
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    The science of inheritance is being turned
    on its head.
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    We're changing the view of what
    inheritance is.
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    This small Swedish town may hold
    the evidence to launch a medical
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    revolution. Överkalix lies huddled on the
    edge of the Arctic Circle
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    Inaccessible and remote, it was cutoff
    from the rest of the world for most of
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    its history. Marcus Pembrey has traveled
    here to meet his colleague, Olov Bygren.
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    They believe that the stories lying
    buried in this graveyard may hold the
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    proof to their radical ideas.
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    Here we have multiple generation in
    the same grave.
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    This group of people could really
    contribute to a sea of change in the
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    way we think about inheritance.
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    They have come to this churchyard to
    find grandmothers and granddaughters,
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    grandfathers and grandsons. Connecting
    people who lived almost a hundred years
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    apart, in entirely new ways. Uncovering
    links that confound scientific thinking.
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    Up until now, inheritance was just, just,
    the genes, the DNA sequence. I suspect
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    that we're going to be able to demonstrate
    that the inheritance is more than that.
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    This is a grandson as it were in our
    study...
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    It is the culmination of more than
    twenty years of work, and for the
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    first time Pembrey is confronting the
    magnitude of their discovery.
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    It has really come alive for me, coming
    here, more than I had expected it to.
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    I'm really quite sort of emotional about
    it. Wonderful!
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    Marcus Pembrey is one of a select brand of
    scientists, a brand that is willing to
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    challenge an orthodoxy. They believe the
    lives of our parents, grandparents, and
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    even our great grandparents can directly
    effect our well-being, despite never
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    experiencing these things ourselves.
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    To many of people, these ideas are
    regarded as scientific heresy.
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    You cannot predict where these important
    will be, the only thing that you can do is
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    follow your instinct.
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    Conventional biology has always believed
    that our genetic inheritance is set in
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    stone at the moment of our conception. At
    that instant, we receive a set of
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    chromosomes from both our mother and our
    father.
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    Within these chromosomes are the genes,
    strips of coded DNA, the basic unit of
    inheritance.
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    After conception, it was presumed assumed that our
    genes were locked away inside every cell
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    of the body, protected untouched from the
    way you live.
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    So what you do in your life may effect you,
    but your genes remain untainted, unchanged
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    for future generations.
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    In classic genetics, your parents and
    grandparents simply pass on their genes,
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    the experiences they accumulated in a
    lifetime are never inherited, lost forever
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    as the genes pass untouched generation
    after generation.
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    The biology of inheritance was a reassuringly
    pure process, or so it seemed.
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    In the early '80's, Marcus Pembrey headed
    the clinical genetic department at
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    Great Ormond Street Hospital for Children.
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    He was frequently treating families with
    unusual genetic conditions.
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    We were constantly coming across families
    which didn't fit the rules, that didn't fit
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    any of the patterns that genetics were
    supposed to fit, so you think of
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    chromosome abnormalities and, uh, you
    check the chromosomes and they are normal.
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    So you then to start imagining as it were,
    you know, what might be underlying this
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    and you are really driven to try and work
    it out because the families really needed
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    some help.
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    The more families he saw, the more the
    rules of inheritance appeared to break
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    down.
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    Diseases and conditions that simply didn't
    fit with the textbook conventions.
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    One condition in particular caught his eye,
    Angelman Syndrome.
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    Named after Harry Angelman, the
    pediatrician who first described Angelman

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    Syndrome, he described them as "happy
    puppet children" because it described some
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    of their apparent features. They have a
    jerky movement when they are walking.
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    These children have no speech, they are
    severely incapacitated in terms of learning,
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    but are uncharacteristically happy,
    they're smiling all of the time.
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    The condition was caused by a genetic
    fault, a key sequence of DNA was missing,
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    deleted from chromosome 15.
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    Then we came across a paradox; at the same
    the same change, the same deletion,
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    was clearly associated with a quite
    different syndrome, much milder in terms
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    of impairment, the Prader-Willi Syndrome.
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    These children are characterized by being
    very floppy at birth, but once they
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    started eating properly they then had
    an insatiable appetite and would get
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    very, VERY large.
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    What Pembrey saw simply made no sense.
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    Here were two completely different
    diseases, Angelman Syndrome and
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    Prader-Willi Syndrome being caused by
    exactly the same genetic fault.
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    So here we were in a bizarre situation
    really.
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    How could anyone propose that the same
    deletion cause a different syndrome?
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    It appeared to Pembrey as if the simple
    view of inheritance was beginning to
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    unravel. But his doubts were contrary to
    the tide of optimism sweeping the scientific
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    community.
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    In the early 1990's, the biggest project
    ever undertaken in human biology was
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    captivating the world.
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    The human genome project will be seen as
    the outstanding achievement in the history
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    of Mankind.
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    The human genome project was to be the
    pinnacle of work on understanding human
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    genes and genetics. It seemed as if the
    secrets of life were at our fingertips.
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    The human genome is like a bible where
    everything was written down. The hope,
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    the expectation, was once we had that book
    in front of us, and all the letters we could
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    just read down the pages, then we would
    understand how the body was put together.
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    It would offer a complete understanding of
    human biology at a molecular level.
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    The hope was that once the code was written
    down, scientists could find the genetic cause
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    and cure for every disease.
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    We were thinking of genes in a very
    mechanical way; we were thinking of them
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    just in terms of the sequence of the letters.
    We were working out what all the letters
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    were in the book.
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    Scientists estimated that the human genome,
    the book of life,
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    would contain around 100,000 genes.
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    And then when they started sequencing they
    realized there may be fewer than 100,000
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    genes, then it popped down to 60,000, then
    it popped down to 50,000... It slowly went
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    down to a much smaller number. In fact,
    we found that the human genome is
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    probably not as complex and doesn't have
    as many genes as plants do.
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    So that then made us really question, well,
    "if the genome has less genes in this
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    species than in this species, and we're more
    complex, potentially, what is going on here?"
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    Now scientists estimate there are probably
    less than 30,000 genes.
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    We believed, I believed naively, that we would
    be able to find the genetic components of

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    common diseases. That's proven to be very
    difficult, as the idea of one gene, one
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    disease does not explain it all.
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    30,000 genes didn't appear to be enough
    to explain human complexity, there had
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    to be something they missed.
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    The first hints of what was missing lay in
    the curious curious paradox of the
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    Prader-Willi and Angelman Syndromes.
    Two quite different diseases caused by
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    exactly the same genetic fault. When
    Pembrey looked at the inheritance
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    patterns for the conditions, he noticed
    something even stranger...
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    What really mattered was the origin of
    the chromosome 15 that had the deletion.
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    If the deletion was one the chromosome 15
    that the child inherited from the father,
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    then you had Prader-Willi Syndrome. If the
    deletion was inherited from the mother,
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    then you the Angelman Syndrome.
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    It was a complete surprise that the same
    missing strip of DNA could cause one
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    disease when it came from the mother, and
    a completely different disease when it
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    came from the father. It's as if the genes knew
    where they came from.
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    You're got a developing fetus manifesting
    this condition, how does the chromosome

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    15 know where it came from? There must
    have been a tag or imprint impressed on
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    that chromosome during egg or sperm
    formation in the previous generation to
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    say "hi, I came from mother," or "I came
    from father" and we are functioning
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    differently. And that is the key, although
    the DNA sequences the same, the
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    different sets of genes were being silenced
    depending on if they came from the
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    mother or the father.
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    It showed there was clearly more to
    inheritance than simply the coded DNA.
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    We then realized we were dealing with
    what is now known as genomic imprinting.
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    What genomic imprinting means, is in a
    nutshell, genes have a memory of where
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    they came from.
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    Something other than just the DNA was
    capable of moving between generations.
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    It was a tantalizing glimpse into this
    unknown and unexpected world. A
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    hidden layer acting on, and able to
    directly control how our genes function.
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    It meant that inheritance was not simply about
    which genes you inherited, but whether
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    those genes were silenced, switched on
    or off.
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    And you can think of it like a lightswitch...
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    Dawn the gene, the light is on, the gene is
    active, it makes the cell do a certain thing.
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    Or, the light switch is off and everything
    is dark, it is off. The gene remains turned
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    on or off and that gives the cells their
    identity.
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    The activity of genes was being controlled
    by a switch, the attachment of a certain
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    chemical that dictated whether a gene was
    switched on, or off.
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    Whether those genes are turned on or off
    is called epigenetics.
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    Epigenetics...act...upon the...genes.
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    Not only is the sequence important of the
    DNA, which we've studied for a long time,
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    the past few decades, but we now understand
    that in addition to that there is this underlying
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    epigenetic phenomena that allows the genes
    to get turned on or off.
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    Epigenetics could explain how a human could
    be created with less than 30,000 genes, and
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    why the genome project didn't provide all
    of the answers.
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    Now if we actually put epigenetics on top
    of it, where it makes it much more
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    complicated if genes get activated to a
    certain level and so forth, then you
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    have a complexity that can start explain biology
    much more effectively than the simple
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    sequence of the DNA.
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    So clearly we have additional levels of
    complexity that we now need to
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    understand that are well beyond the DNA.
    The next huge challenge for modern biology
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    is to now decipher the epigenetic code, to
    understand all the combinations of switches
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    that exist.
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    An accurate chemical map of the human
    genome tells us surprisingly little about
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    how it actually works. Transcribing the
    code of the genes, the genome project,
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    is not an end, but simply a beginning.
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    If inheritance was not just about DNA,
    if these gene switches were so important,
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    just what could turn them on, or off?
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    Stepahnie and Amon Mullins have two
    children, Kiren and Charlotte.
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    When you are trying to conceive and you
    see all of your friends around you getting
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    pregnant, having children, as each month
    goes on you become more and more desperate.
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    Doctors recommended IVF treatment.
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    In the UK alone, around 8,000 babies are
    conceived every year using assisted
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    reproduction techniques like IVF. After
    the third attempt, Stephanie became
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    pregnant with Kiren.
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    At the time, they didn't really highlight
    any risk to us, and then we went for a
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    routine scan, and I did feel that the scan
    was taking an awful long time.
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    Basically what they found was something
    called an exomphalos on Kiren's abdomen
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    which basically means that part of the
    bowel is still on the outside of the
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    abdomen.
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    Doctors suspected that Kiren might be
    suffering from Beckwith Wiedemann
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    syndrome, a rare condition where babies
    are born very large, have oversized
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    tongues, and high risk of developing
    childhood cancers.
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    They couldn't say for 100% that the baby
    did have Beckwith Wiedemann syndrome,
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    but it was showing signs, they could see
    his tongue protruding on the scan and
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    they said he had very big thighs... But
    until Kiren was born, we didn't know how
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    severely effected he would be.
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    When Kiren was born it was clear he did
    have Beckwith Wiedemann syndrome.
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    Within a few hours of the birth, Kiren had
    to have surgery to put the bowel that was
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    basically on the outside of the abdomen
    put back inside and repaired.
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    Kiren also had surgery to reduce the size
    of his tongue and every few months he has
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    scans to check for tumors.
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    Cases of Beckwith Wiedemann syndrome caught
    the attention of Wulf Reich.
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    Wulf Reich worked in developmental genetics.
    He was fascinated by this emerging epigenetic
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    ghost world. He wanted to know what could
    throw the switches on or off.
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    To his surprise, he found by simply placing
    a mouse embryo in a petri dish could cause
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    genes to switch on or off.
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    After we had seen how relatively easy it
    was to change the switches in mouse embryos,
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    we thought perhaps it could be the same in
    human embryos.
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    We though in IVF you have the embryo for a
    brief period of time in a culture dish, and so we
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    were asking the question whether as with
    the mouse embryo, just the mere fact of
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    having human embryos in a culture dish or
    having been manipulated could alter their
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    genetic switches.
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    Wulf knew that Beckwith Wiedemann syndrome
    was caused by a faulty switch.
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    So what we were looking at was a group of
    babies, children, that had the
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    Beckwith Wiedemann syndrome. What proportion
    of those had been conceived with IVF?
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    Could IVF be switching genes on or off?
    Could IVF itself causethe syndrome?
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    What we found was an increased occurrence
    of this epigenetic syndrome in the IVF
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    population.
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    Although the disease is extremely rare,
    the chance seemed to increase 3-4 times
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    with IVF. It seemed the simple act of
    removing the embryo from its natural
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    environment could trigger the disease.
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    And we did feel frustrate that Kiren had
    Beckwith Wiedemann syndrome because we
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    had IVF, but at that time it seemed like the
    right decision to make.
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    And I think we should look again at the IVF
    procedures, the conditions that are being
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    used, and carry out better and more precise
    experiments to see how we can avoid
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    throwing these epigenetic switches.
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    Wulf had shown that simple changes in the
    environment could switch a gene on or off,
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    but there was more...
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    Everyone thought that any altered switches
    could not be inherited. He took some mice
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    with altered gene switches and bred them.
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    Our expectation was that as the altered
    genome was passed to the children that
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    any epigenetic changes would be wiped
    clean.
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    When he looked at the gene profile of the
    offspring, he was amazed.
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    every
    You have these dots you are looking at,
    and each dot tells you that a gene was on.
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    And all of a sudden someone said "wow,
    look at that!"
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    The epigenetic switch thrown in one
    generation, was clearly also present in
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    the second generation.
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    Nobody had seen this kind of thing before,
    and everyone looking at this gel was saying
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    "no, that can't be right. This must be the
    wrong gel." You know, how you get excited
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    about it and then you thing this is wrong,
    you're not on the right track. And we were
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    very excited, as excited as scientists
    ever get.
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    This meant the genes were not locked away,
    a simple environmental event could effect
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    way genes worked, and that could be inherited.
    It was if a memory of an event could be
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    passed down through generations. It was
    something many scientists regarded as
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    impossible. If this effect could be observed
    in humans, the implication would be profound.
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    It would mean that what we experience could
    effect not just us, but our children
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    and our grandchildren.
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    While these observations were emerging
    from laboratories, Pembrey was still
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    working at Great Ormond Street. He began
    to wonder why these links between
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    generations would exist.
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    Now my reputation was a made as a clinical
    geneticist, so I was much freer to speculate
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    outside my main career. I also like to stir
    things up a bit, and it amuses me to
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    speculate because I have nothing to lose,
    and if I'm right, well then that's very
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    amusing (laughs).
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    He speculated why genes would
    carry a memory from one generation
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    to a next. What evolutionary purpose
    could it serve?
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    Maybe imprinting was used as a
    means of some trans-generational adaptation.
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    He thought it could be used by a mother to
    send messages to her baby in the next
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    generation.
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    Something that always troubled me since I
    was a medical student was what stops the
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    baby's head jamming up in the birth canal?
    The baby of course was grown in one
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    generation, but the mother's pelvis was
    grown in the previous generation.
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    But what if the mother was starving as she
    was growing, so she had a small pelvis?
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    Maybe her her eggs had captured that
    information and were instructing the growth
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    genes of the future babies to not work so
    much and the baby to not grow too much, so
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    as not to jam up the birth canal, so there
    was some coordination between the growth
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    of two generations. That struck me as
    highly reasonable.
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    He published his ideas in a largely obscure
    journal and forgot about it. After all,
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    there was no evidence for any of this, it
    was pure speculation.
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    Then four years later, Marcus received as
    email from a doctor in Sweden.
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    It really came as a bolt out of the blue,
    I just got an email in May 2000 saying my
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    paper was the only thing he could find in
    the literature that in any way sort of
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    tied-in with his basic observation.
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    The email was sent by Olov Bygren. He was
    studying the population records of an
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    obscure town in Sweden, Överkalix. What
    made these records unique were their
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    detail; they recorded births and deaths
    over hundreds of years. But they also
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    provided accurate details of the harvests.
    More significantly, Överkalix position on
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    the Arctic Circle meant that it was
    particularly vulnerable to famine.
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    In the 19th Century, this was a very
    isolated area, they could not have any
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    from the outside as it was so poor they
    had a hard time when there was a famine,
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    and they really had a good time when the
    harvests were good.
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    Bygren began seeing links between
    generations that confounded his expectations.
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    I sent Marcus Pembrey an email saying we
    had some data that could interest him.
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    I was extremely excited to get this
    completely out of the blue, and for the
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    first time it seemed there was some data
    that we could really begin to explore, so
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    that was the beginning of our collaboration.
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    Överkalix offered Pembrey a unique
    opportunity, to see if the events that
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    happened in one generation could effect
    another, decades later.
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    While Pembrey and Bygren sifted through
    their Överkalix data, someone else had
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    stumbled on another group that caught
    them by surprise.
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    Rachel Yehuda is a psychologist. She's
    interested on how people respond to stress.
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    Trans-generational effects were not on my
    radar at all, until we opened up a clinic
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    for the treatment of Holocaust survivors.
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    While treating the Holocaust survivors for
    stress, she was surprised that many of the
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    children of the survivors were they
    themselves suffering stress effects.
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    About five children of Holocaust survivors
    were calling us for every Holocaust
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    survivor. What these children said was that
    they were casualties of the Holocaust, too,
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    that they had been effected by the
    Holocaust indirectly.
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    She was convinced that the stress in the
    children was caused by the continual
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    retelling of the stories by their parents.
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    Our studies had really convinced me that
    it were the later experiences of the child
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    as the child was growing up, bombarded by
    years and years of symptoms from the parents
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    that accounted for the effect that we
    observed.
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    However, in Edinburgh, Johnathan Seckl
    was interested in stress exposure in
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    pregnant women and wondered if stress
    effects could be transmitted to their
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    children. He started some experiments with
    pregnant rats to see if exposing them to
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    stress hormones had any effect on their
    offspring.
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    And we found for the rest of their lifespan,
    those animals themselves had altered
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    stress responses and showed behavior that
    looked like anxiety.
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    To see if this was infecting the genes
    themselves, he decided to breed them and
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    see if the stress effects could be found in
    generations never exposed to the stress
  319. Nesynchronizované
    hormone.
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    And their daughters and sons also go the
    propensity for abnormal stress responses.
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    For Seckl, the only explanation was that
    a stressful even was throwing the switch
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    on a gene, that was then being inherited.
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    His work might have stopped there, until
    world events took a hand. When on 9/11 the
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    planes crashed and the towers came down,
    Yehuda and Seckl were critically aware of
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    the potential of the impact to be far
    reaching, even effecting generations yet
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    to be born. Aelsa Gillium was working in
    a building next to the towers.
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    As I left my building coming out through
    the doors, there was a lot of ash floating
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    through the air, and some office papers.
    I knew if I looked up, I may see somehting
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    I didn't want to see. Just the thought that
    people had died close to me, I broke down.
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    I got very upset. I wanted to get out of
    the environment. Being pregnant, I did not
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    want to open myself up to more emotional
    uncertainty and emotional distress.
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    After the events of 9/11 unfolded, Yehuda
    and Seckl teamed up to study women, like
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    Aelsa, who were pregnant at the time.
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    There were a lot of different opportunities
    to study what the effects of 9/11 would be
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    on the children who might be born to
    parents who developed post-traumatic
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    stress disorder in response to 9/11, and
    particularly those who had been exposed
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    in utero.
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    When exposed to a stressful event, a
    person produces cortisol, a hormone that
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    helps regulate the body's response to that
    stress. If cortisol levels are too low, a
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    person finds coping with stress very
    difficult and are prone to PTSD,
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    Post-Traumatic Stress Disorder. But could
    this effect be transmitted to their offspring?
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    They found nearly 200 women, of whom, a
    number had actually been in the twin towers.
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    About half of them developed PTSD. We then
    looked at those women and found they had
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    abnormal cortisol in their saliva. The most
    striking result was so did their babies. The
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    argument in the Holocaust survivors had
    been their children show abnormal stress
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    hormones because they themselves had
    been stressed by listening to this tale
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    recounted by their parents of their awful
    exposures during the 1940's. That could
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    not be the case with the 9/11 survivors,
    these babies were one year old.
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    Not only did infants have lower cortisol
    levels, but they were different depending
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    on how pregnant the mother was on 9/11.
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    The main effect was only seen with mothers
    with PTSD who were pregnant in the last
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    third of pregnancy. Mothers with equal
    levels of PTSD who were in the first and
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    second third of pregnancy at 9/11, there
    was very little effect on the babies cortisol.
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    It suggested to us that it couldn't just
    be about genetics, but there was something
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    that was being transmitted in the late
    of pregnancy where the mother's symptoms
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    were having some effect on the development
    on the offspring's cortisol system.
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    It appeared that epigenetics might be
    responsible, that an event had altered
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    the stress response in the children.
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    What these findings did was suggest to us
    we needed to be looking where we hadn't
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    even considered looking before.
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    To know for certain this was an epigenetic
    effect, they'll need to be sure their
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    observations were't simply due to high
    levels of stress hormones in the womb.
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    Now, here is the bit where we have to
    speculate,
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    the animal work would suggest that this
    might then persist into the next generation.
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    If they find the same stress effects in
    the children's children of 9/11, then it
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    it will be clear that a genetic memory of
    a stressful event can travel through the
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    generations.
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    That's the key thing next to find out; the
    9/11 population will be very, very
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    important for us to be able to follow what
    is a single, discreet event.
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    the work of Yehuda and Seckl offers
    tantalizing evidence of solid proof of
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    inherited epigenetic effects in humans.
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    But they need data that extend beyond
    just one generation.
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    The only way forward was to look back to
    the past. In Sweden, Pembrey and Bygren
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    had data that provided the chance to study
    the effects of famine through many
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    generations.
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    Olov Bygren was looking to see if poor
    nutrition had an effect on health, when
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    he stumbled on something curious.
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  381. Nesynchronizované
    It appeared that a famine could effect
    people almost a hundred years later,
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    even if they never suffered a famine
    themselves. He wanted to know how
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    this might be possible, so he asked
    Michael Pembrey.
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    First he reported that the food supply
    of the ancestors was effecting the
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    mortality rate, or longevity, of the
    grandchildren. So I was very excited, I
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    responded immediately.
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    Pembrey had a hunch that the incidence of
    one disease, diabetes, might be an
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    indicator that epigenetics was involved.
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    Specifically, I wanted to know the results
    of the diabetes, because this is one I
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    thought might involve the imprinting.
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    So Olov trolled the records for any deaths
    due to diabetes, and then looked back
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    to see if there was anything unusual about
    the diet of their grandparents.
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    A few months later, he emailed me back to
    say indeed they had shown a strong
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    association between the food supply of the
    father's father and the chance of diabetes
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    being shown on the death certificate of
    the grandchild. So of course, I was really
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    rather excited by that because it really
    did look as though there was some
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    trans-generational effect going on there.
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    It looked as if there were clear links
    through the generations, between
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    grandparents and grandchildren.
    They found that the life expectancy of
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    grandchildren was being directly effected
    by the diet of the grandparent. It
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    appeared that Overkilex held the key to
    the first evidence of epigenetic
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    inheritance in humans.
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    It really did look as if there was some
    new mechanism transmitting environmental
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    exposure information from one generation
    to the next.
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    Because these ideas were so heretical,
    Pembrey knew the results could be
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    dismissed as nothing more than a curiosity.
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    They needed to get an understanding of
    how this was happening, how could the
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    grandparent capture the information that
    effecting the grandchildren?
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    We wanted to tease out when you could
    trigger in the ancestor a
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    trans-generational response.
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    So he and Bygren went back to the data
    and looked again. The more they looked,