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So, it all came to life
in a dark bar in Madrid,

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and as I was stepping into the bar,
I encountered my colleague from McGill,

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00:00:24,911 --> 00:00:26,271
Michael Meaney.

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00:00:27,282 --> 00:00:29,272
And we're drinking a few beers,

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00:00:29,692 --> 00:00:33,501
and like scientists do,
he told me about his work.

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He told me that he is interested
in how mother rats

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lick their pups after they are born.

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And I was sitting there and saying,
"This is where my tax dollars are wasted,

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(Laughter)

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00:00:50,432 --> 00:00:53,302
on this kind of soft science."

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But as the beer got more intense
and the alcohol gets into the brain,

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you become more receptive,
and he started telling me

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that the rats, like humans,
lick their pups in very different ways.

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Some mothers do a lot of that,

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some mothers do very little,

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and most are in-between.

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But what's interesting about it

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is that when he follows these pups
when they become adults,

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like years in human life,
long after their mother has died,

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they are completely different animals.

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The animals that were licked
and groomed heavily -

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the high licking and grooming -
are not stressed,

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they have different sexual behavior,
they have a different way of living,

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than those that were not treated
as intensively by her mother.

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So, then I was thinking to myself,

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Is this magic?

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How does this work?

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I'm a biochemist.

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I believe that there are chemical
explanations to nature.

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I was working in a field
called 'epigenetics,'

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but before I jumped into that conclusion,
we had to do another experiment.

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"Is this genetic?" a geneticist
would like you to think.

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Perhaps the mother
had the 'bad mother' gene

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that caused her pups to be stressful,

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and then it was passed
from generation to generation;

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it's all determined by genetics.

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Or is it possible that something else
is going on here?

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In rats, we can ask
this question and answer it.

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So, what we did
is a cross-fostering experiment.

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You essentially separate the litter,
the babies of this rat, at birth,

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to two kinds of fostering mothers,

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not the real mothers,
but mothers that will take care of them:

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high-licking mothers
and low-licking mothers.

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And you can do the opposite
with the low-licking pups.

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And the remarkable answer was,

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it wasn't important what gene
you got from your mother.

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It was not the biological mother
that defined this property of these rats,

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it is the mother
that took care of the pups.

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So, how can this work?

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And as I told you, I am an epigeneticist.

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I am interested in how genes are marked

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00:03:26,830 --> 00:03:30,410
by a chemical mark during embryogenesis,

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00:03:30,410 --> 00:03:33,239
during the time we're in
the womb of our mothers,

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00:03:33,239 --> 00:03:37,011
and decide which gene
will be expressed in what tissue.

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Different genes are expressed in the brain
than in the liver and the eye.

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And we thought,

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is it possible that the mother
is somehow reprogramming

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the gene of her offspring
through her behavior?

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We spent ten years,

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and we found that there
is a cascade of biochemical events

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by which the licking and grooming
of the mother, the care of the mother,

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is translated to biochemical signals
that go into the nucleus and into the DNA,

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and program it differently.

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So now the animal
can prepare itself for life.

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Is life going to be harsh?

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Is there going to be a lot of food?

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Are there going to be
a lot of cats and snakes around?

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Or will I live in
an upper class neighborhood

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where all I have to do
is behave well and proper,

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and that will gain me social acceptance?

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And now, one can think about how important
that process can be for our lives.

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We inherit our DNA from our ancestors.

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The DNA is old;
it evolved during evolution.

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But it doesn't tell us if you
are going to be born in Stockholm,

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where the days are long in summer
and short in the winter,

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or in Ecuador, where there are an equal
number of hours for day and night

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all year around, and that has such
an enormous [impact] on our physiology.

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00:05:03,721 --> 00:05:08,130
So, what we suggest is perhaps
what happens early in life,

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those signals that come
through the mother tell the child

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what kind of social world
you are going to be living in.

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Is it going to be harsh and you better
be anxious and be stressful?

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Or is it going to be an easy world
and you have to be different?

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Is it going to be a world
with a lot of light or a little light?

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Is it going to be a world
with a lot of food or a little food?

85
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If there's no food around,

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you better develop your brain
to binge whenever you see a meal,

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or store every piece of food
that you have as fat.

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So, this is good;
evolution has selected this

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to allow our fixed old DNA to function
in a dynamic way in new environments.

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But sometimes things can go wrong.

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For example, if you're born
to a poor family and the signals are

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'You better binge, you better eat every
piece of food you're going to encounter.'

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But now we humans,
in our brain, have evolved,

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have changed evolution even faster.

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Now you can buy
a McDonald's [hamburger] for $1.00.

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And therefore, the preparation
that we had by our mothers

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is turning out to be maladaptive.

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The same preparation that was supposed to
protect us from hunger and famine

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is going to cause obesity,
cardiovascular problems,

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and metabolic disease.

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So, this concept that genes
could be marked by our experience,

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especially the early life experience,

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can provide us a unifying explanation
of both health and disease.

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But is it true only for rats?

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The problem is, we cannot
test this in humans,

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because ethically, we cannot administer
childhood adversity in a random way.

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So, if a poor child
develops a certain property,

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we don't know whether
this is caused by poverty,

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or whether poor people have bad genes.

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So, geneticists will try to tell you

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that poor people are poor
because their genes made them poor.

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Epigeneticists will tell you
poor people are in a bad environment,

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or impoverished environment

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that creates that phenotype,
that property.

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So, we moved to look
into our cousins, the monkeys.

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My colleague Stephen Suomi has been
rearing monkeys in two different ways.

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Randomly separated
the monkey from the mother

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and reared her with a nurse
in surrogate motherhood conditions.

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So, these monkeys didn't have a mother,
they had a nurse.

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And other monkeys were reared
with their normal, natural mothers.

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And when they were old,
they were completely different animals.

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The monkeys that had a mother
would not care about alcohol,

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they were not sexually aggressive.

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The monkeys that didn't have a mother
were aggressive, were stressed,

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and were alcoholics.

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So, we looked at their DNA
early after birth,

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to see, is it possible
that the mother is marking?

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There is a signature of the mother
in the DNA of the offspring.

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These are, today, 14 monkeys,

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and what you see here is the modern way
by which we study epigenetics.

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We can now map those chemical marks,
which we call methylation marks,

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on DNA at a single nucleotide resolution,
we can map the entire genome.

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We can now compare the monkey
that had a mother and not.

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And here is a visual presentation of this.

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What you see is the genes
that got more methylated are red;

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the genes that got
less methylated are green.

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You can see many genes are changing.

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Because not having a mother
is not just one thing,

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if affects the whole way.

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It sends us signals about the whole way
your world is going to look

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when you become an adult,

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and you can see the two groups of monkeys
extremely well separated from each other.

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How early does this develop?

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These monkeys already
didn't see their mother

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so they had a social experience.

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Do we sense our social status
even at the moment of birth?

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So, in this experiment,

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we took placentas of monkeys
that had different social status.

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What's interesting about social rank,
is that across all living beings,

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they will structure
themselves by hierarchy.

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Monkey number one is the boss.

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Monkey number four is the peon.

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And you put four monkeys in a cage,
there will always be a boss,

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and always be a peon.

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And, what's interesting,
is that monkey number one

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is much healthier than monkey number four.

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And if you put them in a cage,
monkey number one will not eat as much,

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monkey number four will eat as much.

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And what you see here
in this methylation mapping,

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the animals that had a high social status,

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versus the animals
that did not have a high status.

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So, we are born already knowing
the social information,

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and that social information
is not bad or good,

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it just prepares us for life

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because we have to program
our biology differently

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if we're in a high or low social status.

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00:10:26,087 --> 00:10:28,068
But how can you study this in humans?

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We can't do experiments;
we can't administer adversity to humans.

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But God does experiments with humans,
and it's called natural disasters.

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One of the hardest natural disasters
in Canadian history

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happened in my province of Quebec.

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It's the ice storm of 1998.

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We lost our entire electrical grid
because of an ice storm

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when the temperatures were
in the dead of winter in Quebec,

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-20 to -30, and there were
pregnant mothers during that time.

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And my colleague, Suzanne King,
followed the children of these mothers

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for 15 years.

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00:11:07,621 --> 00:11:11,923
And what happened was
that as the stress increased,

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and here we had objective
measures of stress:

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How long you were without power;

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00:11:16,691 --> 00:11:18,991
where did you spend your time?

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Was it in your mothers-in-law apartment
or in some posh country home?

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All these added up
to a social stress scale

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00:11:26,592 --> 00:11:31,303
and you can ask the question,
how did the children look?

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It appears that as stress increases,
the children develop more autism,

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00:11:35,931 --> 00:11:41,642
they develop more metabolic diseases,
and they develop more autoimmune diseases.

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00:11:41,921 --> 00:11:44,135
And we would map the methylation state

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and again, you see the green genes
becoming red as stress increases.

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The red genes becoming green
as stress increases,

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00:11:53,342 --> 00:11:58,303
an entire rearrangement of the genome
in response to stress.

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So, if we can program genes,

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00:12:01,923 --> 00:12:06,253
if we are not just the slaves
of the history of our genes,

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00:12:06,253 --> 00:12:09,265
but they can be programmed,
can we deprogram them?

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00:12:09,783 --> 00:12:13,905
Because epigenetic causes
can cause diseases like cancer,

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00:12:13,905 --> 00:12:18,076
metabolic disease
and mental health diseases.

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00:12:18,326 --> 00:12:21,276
Let's talk about cocaine addiction.

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Cocaine addiction is a terrible situation,

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that can lead to death
and to loss of human life.

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00:12:29,847 --> 00:12:35,077
We ask the question,
can we reprogram the addicted brain

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00:12:35,077 --> 00:12:40,390
to make that animal non-addicted anymore?

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00:12:40,609 --> 00:12:46,938
We used a cocaine addiction model
that recapitulates what happens in humans.

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00:12:46,938 --> 00:12:51,579
In humans, you're in high school,
some friends suggest you use some cocaine,

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00:12:51,579 --> 00:12:53,669
you take cocaine, nothing happens.

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00:12:53,669 --> 00:12:57,800
Months pass by; something reminds you
of what happened the first time,

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00:12:57,800 --> 00:13:00,690
a pusher pushes cocaine,
and you become addicted,

206
00:13:00,690 --> 00:13:02,548
and your life has changed.

207
00:13:02,548 --> 00:13:03,988
In rats, we do the same thing.

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00:13:03,988 --> 00:13:08,637
My colleague Gal Yadid, he trains
the animals to get used to cocaine,

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00:13:08,637 --> 00:13:11,849
then for one month, no cocaine.

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00:13:11,849 --> 00:13:15,358
And then he reminds them of the party
when they saw cocaine the first time

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00:13:15,358 --> 00:13:18,411
via cue - the colors of the cage
when they saw cocaine,

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00:13:18,411 --> 00:13:20,071
and they go crazy.

213
00:13:20,071 --> 00:13:23,768
They will press the lever
to get cocaine till they die.

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00:13:24,308 --> 00:13:28,788
We first determined that the difference
between these animals

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00:13:28,788 --> 00:13:31,409
is that during that time,
when nothing happens,

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00:13:31,409 --> 00:13:34,980
there's no cocaine around,
their epigenome is rearranged,

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00:13:34,980 --> 00:13:38,099
their genes are re-marked
in a different way,

218
00:13:38,099 --> 00:13:39,610
and when the cue comes,

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00:13:39,610 --> 00:13:44,875
their genome is ready
to develop this addictive phenotype.

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00:13:44,875 --> 00:13:51,661
So, we treated these animals with drugs
that either increase DNA methylation,

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00:13:51,661 --> 00:13:53,682
which was the epigenetic mark to look at,

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00:13:53,682 --> 00:13:57,373
or decrease epigenetic markings.

223
00:13:57,373 --> 00:14:00,652
And we found that
if we increase methylation,

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00:14:00,652 --> 00:14:05,025
these animals go even crazier,
they have even more craving for cocaine.

225
00:14:05,025 --> 00:14:10,634
But if we reduce the DNA methylation,
the animals are not addicted anymore,

226
00:14:10,634 --> 00:14:12,280
we have reprogrammed them.

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00:14:12,280 --> 00:14:16,923
And the fundamental difference between
an epigenetic drug and any other drug

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00:14:16,923 --> 00:14:19,055
is that with epigenetic drugs

229
00:14:19,055 --> 00:14:23,435
we essentially remove
the science of experience,

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00:14:23,435 --> 00:14:25,451
and once they're gone,

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00:14:25,451 --> 00:14:28,434
they will not come back
unless you have the same experience,

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00:14:28,434 --> 00:14:30,096
so the animal now is reprogrammed.

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00:14:30,096 --> 00:14:34,246
So, when we visited the animals
30 days, 60 days longer,

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00:14:34,246 --> 00:14:37,324
which is, in human terms,
many years of life,

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00:14:37,324 --> 00:14:43,098
they were still not addicted
by a single epigenetic treatment.

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00:14:44,693 --> 00:14:51,153
So, what we learned about DNA:
the DNA is not just a sequence of letters,

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00:14:51,153 --> 00:14:52,903
it's not just a script.

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DNA is a dynamic movie.

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Our experiences are being written
into that movie, which is interactive.

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You're like watching a movie of your life,
with the DNA, with your remote control.

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You can remove an actor, and add an actor.

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So, in spite of the deterministic
nature of genetics,

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you have control
of the way your genes look.

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And this has a tremendous
optimistic message.

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For the ability to now encounter
some of the deadly diseases

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like cancer, mental health,
with a new approach,

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looking at them as maladaptation,

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that if we can epigenetically intervene,
reverse the movie by removing an actor

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and setting up a new narrative.

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So, what I told you today is that our DNA

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is really a combination of two components,
two layers of information.

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One layer of information is old,

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evolved from millions
of years of evolution;

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it is fixed and very hard to change.

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The other layer of information
is the epigenetic layer,

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which is open and dynamic,

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and sets up a narrative
that is interactive.

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So, even though
we are determined by our genes,

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we have a degree of freedom

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that can set up our life
to a life of responsibility.

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Thank you.

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(Applause)