[Music]
if you bang your head usually your skull
absorbs the blow and protects your brain
but what if the blow comes again and
again from deep inside your brain
I think neurodegenerative disease is
that blow and today it's slowly killing
more than 5 million Americans whether
the disease is Alzheimer's Parkinson's
ALS or Huntington's each delivers its
blow and then robs us of our memories
control of our bodies our thought
processes even our personalities for one
of those diseases the source of the
destruction is a single bad gene that
destroys a walnut sized part of your
brain I'm 46 around the age when it
typically begins and if I had that gene
that part of my brain might already be
50% gone yet I could still be standing
here speaking to you as I am now but in
just a few years more than 90 percent of
that part would be destroyed and I'd be
rendered a writhing shell of what I am
today confused irritable and unable to
communicate
George Huntington described this disease
first in his patients in 1872 for six
generations those who had inherited this
single bad gene suffered and died from
it and during those 121 years there was
no progress and no answers but then in
1993 the single gene that causes
Huntington's disease was finally
identified and sequenced I remember
excitement reading the paper that March
with members of the laboratory of human
genetics where I was working
I was 22 and about to enter graduate
school in neuroscience and we were
certain back then that a cure would soon
follow but in the generation since I've
watched an army of neuroscientists
struggle to understand how that gene and
then other genes doom people who have
these neurodegenerative diseases
Institutes of Health and drug companies
spent tens of billions of dollars to
understand the link between these genes
they're bad proteins and the brain cells
called neurons that get sick died and
disappear and yet today there is still
not one single medicine that can slow
stop or reverse these diseases
devastating and invariably fatal neuro
degeneration it's almost unbelievable
we know the genetic code we understand
how proteins build and run cells for the
most part and yet for a disease caused
by a single gene we have barely any
answer for a family member who asks us
what is happening to my dad or to my mom
and when Nancy Freitas 27 year old son
Peter an athlete was diagnosed with ALS
she was horrified to learn that there
was nothing that could slow stop or
reverse his progressive loss of motor
control so she started the worldwide ice
bucket challenge she wanted others to
have more hope for a brighter future and
for a better prognosis than Peter had
received and better than Lou Gehrig
received when he was diagnosed with ALS
in 1939 or Woody Guthrie with
Huntington's in 1952 Ronald Reagan with
Alzheimer's
1994 or Robin Williams with Parkinson's
Lewy body disease in 2013 why is there
no more hope today than there was back
then this is the question I've been
asking myself since graduate school and
my conclusion is we've been focused for
too long on just the neuron it's time we
turned the brain and brain research on
its head and look beyond the neuron
beyond it's bad genes and their bad
proteins for a missing link in the
system within which these genes proteins
and neurons operate the nervous system
I'm convinced the answer lies not just
in showing how neurons can suffer from
genetic disorders but how genes can
suffer from nervous disorders so let me
show you how I think about the brain it
turns out neurons communicate in a kind
of drum language a neuron is electrical
and it generates a small fluctuation in
voltage across its cellular skin that
lasts a few milliseconds but for this
explanation let's just call these
fluctuations beats a neuron beats at
about one to ten beats per second in
idiosyncratic patterns and on each beat
it reaches out with a tiny molecular
drum stick and it strikes another neuron
skin these strikes use a small amount of
energy and crucially no neuron can
directly control any of the strikes that
it receives and the reason is that each
neuron receives between one thousand and
one hundred thousand of these synapse
connections whose strikes come from
other neurons and their beats all over
the brain the human brain is made up of
about 100 billion neurons so that's
about 1 trillion new beats arising every
second
and on each beat each neuron reaches out
not with one drumstick but with
thousands of drumsticks and strikes
simultaneously thousands of other
neurons all over the brain that's
potentially a quadrillion drumstick
strikes happening across all the
synapses of your brain every second now
with all this activity what fascinates
me the most is that the total amount of
drumming in the brain its total energy
consumption barely varies whether I'm
vigorously speaking to you now or
quietly chilling out afterwards the
system is beating away all the time at
about the same global rate which makes
sense because a neurons genes help to
regulate its tempo but what occurred to
be next got me out of bed at 3:00 a.m.
and set me pacing you see everything
I've told you doesn't explain why during
the brain's resting state activity
neurons don't drum together overwhelm
each other and sabotage the system the
brain has no drum master and so we have
to think of these genes not just inside
a single neuron but within the context
of the entire nervous system by sensing
feedback from the brain these genes
don't just set the tempo they implement
a strategy like a frugal punk rock
drummer drumming on different heads in
different places gig after gig
night after night so that he wears his
drums evenly and his kit lasts a long
time
a healthy brain must control its spatial
patterns of drumming so that it doesn't
wear out any one neuron synapse or gene
in the system based on feedback from the
brain on two neurons synapses and genes
neurons must learn to cooperate
to take turns and to drum evenly like
the hands of a good drummer a healthy
brain must drum evenly so that it's
trillions of synapses last a lifetime
to understand how these strategies for
healthy drumming work I decided to go
back to basics and to go big because of
the way the brain is constructed
drumming anywhere in the brain depends
upon the whole brain and so to
understand feedback from the brain onto
genes and how these strategies succeed
and fail I created a radical brain model
I mapped the brains core components and
I connected them together in a new and
consistent way that I call the grand
loop I discovered that despite all its
complexity the brain can be rendered
elemental this core anatomical circuit
goes back to the Cambrian explosion to a
common ancestor 540 million years ago
why because it includes the core key
structures that all brains have in
common and each of the structures which
are attacked by its own
neurodegenerative disease I think that
this core circuit holds the key to
unlocking these strategies for even
healthy drumming in the brain and I
implemented the model and simulated it
with synapses that adjust themselves
based on feedback and my team members
and I have observed that disturbances in
these adjustments can lead to unusual
patterns in the models drumming I
believe that in the major
neurodegenerative diseases that
disturbances such as these can lead the
brain to drum unevenly and that tissues
can fail with horrible consequences
that's because in the brain a bad gene
an injury or aging can lead to changes
in a circuit that create then reinforce
drumming habits which are bad for the
brains structures these bad brain habits
I think are so subtle that individuals
don't perceive them they don't choose
them and they can't control them and
doctors can't detect them until it's too
late
but once these bad drumming habits
emerge neurons overwhelm each other and
feedback from all over the brain causes
genes to be expressed differently
this turns the brain into a bad drummer
who tears through one location in the
nervous system
killing specific neurons in a specific
tissue in a gruesome and evil way
effectively by beating them to death and
then when the demon drummer shifts and
bad drumming begins wearing a hole in a
new location on the same drum head of
the same drum in the kit what we can
learn from this is that the drum in the
kit which is eventually and completely
destroyed tells us whether the drummer's
name was Alzheimer's Parkinson's ALS or
Huntington's so let me be clear I think
that the brain's core circuit can kill
itself one neuron at a time this is what
we aim to demonstrate using the grand
loop brain circuit model and if I could
go back to 1993 to the table where we
discussed that paper
I'd say before we can understand how
genes cause imbalance in neurons leading
to their death neuroscientists must
understand how the brains core circuit
balances itself and how feedback from
the brain onto neurons
synapses and genes can push the system
to the tipping point now the exciting
news is that we're beginning to make
progress and to unravel these challenges
in Huntington's disease we are
simulating the brain's resting state
activity as well as risky bad brain
habits
in order to propose new ways to
alleviate the stresses on the brain and
on its neurons we want to learn how to
detect these habits early and then break
them with a new kind of medicine that
will finally offer a treatment and even
prevent these diseases and the havoc
that they wreak in the lives of patients
within the grande loops brain circuit
model our missing links for each of the
neurodegenerative diseases my team is
understanding how these feedback
mechanisms can change the circuit and we
do this by pushing the model to the
tipping point again and again until we
expose each of this circuits secret bad
habits our goal is for neuroscientists
and geneticists alike to adopt a global
brain context for their research a
radical brain circuit model with a grand
loop at its core that can spark an
explosion of new knowledge and propel us
to finally find ways to stop any of us
like Nancy freights and her son or Woody
Guthrie and Robin Williams from having
to suffer the ravages of any of these
cruel diseases thank you
[Applause]