How early life experience is written into DNA Moshe Szyf
So it all came to life
in a dark bar in Madrid.
I encountered my colleague
from McGill, Michael Meaney.
And we were drinking a few beers,
and like scientists do,
he told me about his work.
And he told me that he is interested
in how mother rats lick their pups
after they were born.
And I was sitting there and saying,
“This is where my tax
dollars are wasted –
(Laughter)
on this kind of soft science.”
And he started telling me
that the rats, like humans,
lick their pups in very different ways.
Some mothers do a lot of that,
some mothers do very little,
and most are in between.
But what’s interesting about it
is when he follows these pups
when they become adults –
like, years in human life,
long after their mother died.
They are completely different animals.
The animals that were licked
and groomed heavily,
the high-licking and grooming,
are not stressed.
They have different sexual behavior.
They have a different way of living
than those that were not treated
as intensively by their mothers.
So then I was thinking to myself:
Is this magic?
How does this work?
As geneticists would like you to think,
perhaps the mother had
the “bad mother” gene
that caused her pups to be stressful,
and then it was passed
from generation to generation;
it’s all determined by genetics.
Or is it possible that something
else is going on here?
In rats, we can ask
this question and answer it.
So what we did is
a cross-fostering experiment.
You essentially separate the litter,
the babies of this rat, at birth,
to two kinds of fostering mothers –
not the real mothers,
but mothers that will take care of them:
high-licking mothers
and low-licking mothers.
And you can do the opposite
with the low-licking pups.
And the remarkable answer was,
it wasn’t important
what gene you got from your mother.
It was not the biological mother
that defined this property of these rats.
It is the mother that
took care of the pups.
So how can this work?
I am an a epigeneticist.
I am interested in how genes are marked
by a chemical mark
during embryogenesis, during the time
we’re in the womb of our mothers,
and decide which gene will be expressed
in what tissue.
Different genes are expressed in the brain
than in the liver and the eye.
And we thought: Is it possible
that the mother is somehow
reprogramming the gene of her offspring
through her behavior?
And we spent 10 years,
and we found that there is a cascade
of biochemical events
by which the licking and grooming
of the mother, the care of the mother,
is translated to biochemical signals
that go into the nucleus and into the DNA
and program it differently.
So now the animal can prepare
itself for life:
Is life going to be harsh?
Is there going to be a lot of food?
Are there going to be a lot of cats
and snakes around,
or will I live
in an upper-class neighborhood
where all I have to do
is behave well and proper,
and that will gain me social acceptance?
And now one can think about
how important that process can be
for our lives.
We inherit our DNA from our ancestors.
The DNA is old.
It evolved during evolution.
But it doesn’t tell us
if you are going to be born in Stockholm,
where the days are long in the summer
and short in the winter,
or in Ecuador,
where there’s an equal number of hours
for day and night all year round.
And that has such an enormous [effect]
on our physiology.
So what we suggest is,
perhaps what happens early in life,
those signals that come
through the mother,
tell the child what kind of social world
you’re going to be living in.
It will be harsh, and you’d better
be anxious and be stressful,
or it’s going to be an easy world,
and you have to be different.
Is it going to be a world
with a lot of light or little light?
Is it going to be a world
with a lot of food or little food?
If there’s no food around,
you’d better develop your brain to binge
whenever you see a meal,
or store every piece of food
that you have as fat.
So this is good.
Evolution has selected this
to allow our fixed, old DNA
to function in a dynamic way
in new environments.
But sometimes things can go wrong;
for example, if you’re born
to a poor family
and the signals are, “You better binge,
you better eat every piece of food
you’re going to encounter.”
But now we humans
and our brain have evolved,
have changed evolution even faster.
Now you can buy McDonald’s for one dollar.
And therefore, the preparation
that we had by our mothers
is turning out to be maladaptive.
The same preparation that was supposed
to protect us from hunger and famine
is going to cause obesity,
cardiovascular problems
and metabolic disease.
So this concept that genes
could be marked by our experience,
and especially the early life experience,
can provide us a unifying explanation
of both health and disease.
But is true only for rats?
The problem is, we cannot
test this in humans,
because ethically, we cannot administer
child adversity in a random way.
So if a poor child develops
a certain property,
we don’t know whether
this is caused by poverty
or whether poor people have bad genes.
So geneticists will try to tell you
that poor people are poor
because their genes make them poor.
Epigeneticists will tell you
poor people are in a bad environment
or an impoverished environment
that creates that phenotype,
that property.
So we moved to look
into our cousins, the monkeys.
My colleague, Stephen Suomi,
has been rearing monkeys
in two different ways:
randomly separated the monkey
from the mother
and reared her with a nurse
and surrogate motherhood conditions.
So these monkeys didn’t have
a mother; they had a nurse.
And other monkeys were reared
with their normal, natural mothers.
And when they were old,
they were completely different animals.
The monkeys that had a mother
did not care about alcohol,
they were not sexually aggressive.
The monkeys that didn’t have a mother
were aggressive, were stressed
and were alcoholics.
So we looked at their DNA
early after birth, to see:
Is it possible that the mother is marking?
Is there a signature of the mother
in the DNA of the offspring?
These are Day-14 monkeys,
and what you see here is the modern way
by which we study epigenetics.
We can now map those chemical marks,
which we call methylation marks,
on DNA at a single nucleotide resolution.
We can map the entire genome.
We can now compare the monkey
that had a mother or not.
And here’s a visual presentation of this.
What you see is the genes
that got more methylated are red.
The genes that got
less methylated are green.
You can see many genes are changing,
because not having a mother
is not just one thing –
it affects the whole way;
it sends signals about the whole way
your world is going to look
when you become an adult.
And you can see the two groups of monkeys
extremely well-separated from each other.
How early does this develop?
These monkeys already
didn’t see their mothers,
so they had a social experience.
Do we sense our social status,
even at the moment of birth?
So in this experiment,
we took placentas of monkeys
that had different social status.
What’s interesting about social rank
is that across all living beings,
they will structure
themselves by hierarchy.
Monkey number one is the boss;
monkey number four is the peon.
You put four monkeys in a cage,
there will always be a boss
and always be a peon.
And what’s interesting
is that the monkey number one
is much healthier than monkey number four.
And if you put them in a cage,
monkey number one will not eat as much.
Monkey number four will eat [a lot].
And what you see here
in this methylation mapping,
a dramatic separation at birth
of the animals that had
a high social status
versus the animals
that did not have a high status.
So we are born already knowing
the social information,
and that social information
is not bad or good,
it just prepares us for life,
because we have to program
our biology differently
if we are in the high
or the low social status.
But how can you study this in humans?
We can’t do experiments,
we can’t administer adversity to humans.
But God does experiments with humans,
and it’s called natural disasters.
One of the hardest natural disasters
in Canadian history
happened in my province of Quebec.
It’s the ice storm of 1998.
We lost our entire electrical grid
because of an ice storm
when the temperatures
were, in the dead of winter in Quebec,
minus 20 to minus 30.
And there were pregnant
mothers during that time.
And my colleague Suzanne King
followed the children of these mothers
for 15 years.
And what happened was,
that as the stress increased –
and here we had objective
measures of stress:
How long were you without power?
Where did you spend your time?
Was it in your mother-in-law’s apartment
or in some posh country home?
So all of these added up
to a social stress scale,
and you can ask the question:
How did the children look?
And it appears that as stress increases,
the children develop more autism,
they develop more metabolic diseases
and they develop more autoimmune diseases.
We would map the methylation state,
and again, you see the green genes
becoming red as stress increases,
the red genes becoming green
as stress increases,
an entire rearrangement
of the genome in response to stress.
So if we can program genes,
if we are not just the slaves
of the history of our genes,
that they could be programmed,
can we deprogram them?
Because epigenetic causes
can cause diseases like cancer,
metabolic disease
and mental health diseases.
Let’s talk about cocaine addiction.
Cocaine addiction is a terrible situation
that can lead to death
and to loss of human life.
We asked the question:
Can we reprogram the addicted brain
to make that animal not addicted anymore?
We used a cocaine addiction model
that recapitulates what happens in humans.
In humans, you’re in high school,
some friends suggest you use some cocaine,
you take cocaine, nothing happens.
Months pass by, something reminds you
of what happened the first time,
a pusher pushes cocaine,
and you become addicted
and your life has changed.
In rats, we do the same thing.
My colleague, Gal Yadid,
he trains the animals
to get used to cocaine,
then for one month, no cocaine.
Then he reminds them of the party
when they saw the cocaine the first time
by cue, the colors of the cage
when they saw cocaine.
And they go crazy.
They will press the lever to get cocaine
until they die.
We first determined that the difference
between these animals
is that during that time
when nothing happens,
there’s no cocaine around,
their epigenome is rearranged.
Their genes are re-marked
in a different way,
and when the cue comes,
their genome is ready
to develop this addictive phenotype.
So we treated these animals with drugs
that either increase DNA methylation,
which was the epigenetic
marker to look at,
or decrease epigenetic markings.
And we found that
if we increased methylation,
these animals go even crazier.
They become more craving for cocaine.
But if we reduce the DNA methylation,
the animals are not addicted anymore.
We have reprogrammed them.
And a fundamental difference
between an epigenetic drug
and any other drug
is that with epigenetic drugs,
we essentially remove
the signs of experience,
and once they’re gone,
they will not come back
unless you have the same experience.
The animal now is reprogrammed.
So when we visited the animals
30 days, 60 days later,
which is in human terms
many years of life,
they were still not addicted –
by a single epigenetic treatment.
So what did we learn about DNA?
DNA is not just a sequence of letters;
it’s not just a script.
DNA is a dynamic movie.
Our experiences are being written
into this movie, which is interactive.
You’re, like, watching a movie
of your life, with the DNA,
with your remote control.
You can remove an actor and add an actor.
And so you have, in spite
of the deterministic nature of genetics,
you have control of the way
your genes look,
and this has a tremendous
optimistic message
for the ability to now encounter
some of the deadly diseases
like cancer, mental health,
with a new approach,
looking at them as maladaptation.
And if we can epigenetically intervene,
[we can] reverse the movie
by removing an actor
and setting up a new narrative.
So what I told you today is,
our DNA is really combined
of two components,
two layers of information.
One layer of information is old,
evolved from millions
of years of evolution.
It is fixed and very hard to change.
The other layer of information
is the epigenetic layer,
which is open and dynamic
and sets up a narrative
that is interactive,
that allows us to control,
to a large extent, our destiny,
to help the destiny of our children
and to hopefully conquer disease
and serious health challenges
that have plagued humankind
for a long time.
So even though we are determined
by our genes,
we have a degree of freedom
that can set up our life
to a life of responsibility.
Thank you.
(Applause)