[Music]
[Applause]
imagine you start to feel sick maybe
you’re a bit thirsty more than usual
very fatigued using the bathroom a lot
more than usual
perhaps you start getting blurry vision
you suspect it might be diabetes so you
make an appointment with your doctor in
hopes of getting a diagnosis and some
treatment now imagine at this
appointment the very best your doctor
could do is ask you some questions about
your symptoms no blood tests no panels
and then offer you an opinion on your
diagnosis well it may be diabetes and
then prescribe you an angel that
wouldn’t work for the majority of
patients who take it at a dose that
you’d likely have to adjust through
trial and error and repeated visits and
this particular agent will likely make
you feel a lot worse for several weeks
before it starts to make you feel better
sounds pretty unbelievable right in this
day and age of technological advancement
you don’t want your diabetes to be
somebody’s opinion you want a definitive
diagnosis based on a blood test and the
measurement of some chemicals in that
blood and then a treatment strategy
that’s aimed to normalize the levels of
those chemicals and make you feel better
unfortunately as unreal and outdated as
that sounds if you were to make an
appointment to have a mental illness
diagnosis that’s precisely what would
happen mental illnesses are in many ways
much more devastating than bodily
illnesses eight million people die a
year from mental illnesses the W Health
Organization has stated that mental
illnesses such as depression are the
leading cause of disability worldwide
and pose the largest economic burden one
in five Americans is prescribed
antidepressants let’s think about that
for a second that’s a phenomenal number
of people that’s a huge amount of people
and antidepressants don’t work for the
majority of patients who take them and
for reasons that I’m going to get to a
little bit later I’ll outline the fact
that the research community has lost
interest in recent years in developing
better and more improved Lant I present
the present therapies mental illnesses
unlike bodily illnesses are fraught with
shame and taboos and stigma so what’s
the difference between mental illnesses
and diseases of the body what’s the
difference between say diabetes and
depression well the primary difference
is that we understand diseases of the
body much much better than we understand
diseases of the brain let’s talk about
diabetes we know the chemicals that will
mark diabetes amongst others these are
things like glucose and insulin we may
take a blood sample we can measure
glucose and insulin and because we know
what’s wrong we can make a diagnosis
based on those chemicals and we can
develop drugs to target glucose and
insulin and get them back to normal and
make you feel better
unfortunately that’s not the case for in
psychiatric diseases why is that there’s
a strict separation between the body and
the brain it’s called the blood-brain
barrier it exists for a really good
reason it exists to strictly control the
inflow and outflow of chemicals out of
our brains into our brains protects us
from things say like bacteria and
viruses but what it means is that if we
take blood their levels of chemicals in
our blood do not reflect the levels of
chemicals in our brain so to ask
questions of the brain then you would
think perhaps we should take a sample of
the brain while taking a blood sample
what no one likes to do it but it’s a
relatively simple and non disturbing
thing we can’t really think about
opening up someone’s skull and taking a
sample this is potentially devastating
we can’t do that
plus if you think about it you think the
chemicals that we would be looking for
that would likely mark an illness these
are chemicals I’m gonna call
neurotransmitters neurotransmitters are
chemical transmitters that take messages
from one brain cell to another from one
neuron to another they do this through
the tiniest of Junction
that Junction is called a synapse it’s
so small it’s about a thousandth of a
human hair the thousandth of diameter of
a human hair and they do it real
dynamically very very fast they move
from one cell to another within a second
so taking a sample like you wouldn’t
tell us very much about the
functionality of the system to do that
we want to look in on it while it’s
working without disturbing it how do we
do it well over the past decade or so my
research program has been to take a
technical approach to this problem we’ve
developed ultra ultra tiny probes made
out of carbon they’re not a thousandth
of a human hair perhaps our hundredth of
a human hair but they’re so small that
we can directly implant them into tissue
and measure these neurotransmitters as
they go about their business without
disturbing the system so that’s exciting
we have some technology now that we can
use to perhaps ask some questions of the
brain so when it comes to psychiatric
diseases where do we start let’s just
focus on depression what should we
measure well back in the late 70s there
was something called the mono amine
hypothesis of depression and here’s how
it went the idea was that people that
were experiencing depression the levels
of certain of these neurotransmitters in
particular neurotransmitter called
serotonin are lower between the cells
and someone who is not experiencing
depression now mind you this was a
hypothesis with no real way to test it
because the technology wasn’t available
but the hypothesis precipitated the
development of the modern-day
antidepressants that we know as SSRIs
the selective serotonin reuptake
inhibitors the idea is that these drugs
will block a key protein that’s tasked
with clearing serotonin from from the
extracellular space and the idea is that
the serotonin levels will go up and
alleviate depression symptoms the theory
precipitated the development the first
of a type of the first of their type of
these agents was Prozac and since the
late 70s the agents haven’t changed very
much like I said they don’t work for the
majority of patients who take them about
70% of patients do not experience
clinical relief and there
a lot of unwanted side-effects so there
are issues here the hypothesis has been
around there’s been no real way to test
it so till now we still don’t know where
the serotonin is different during
depression or not no one really knows
how these SSRIs work so the fact that we
don’t know what’s wrong in the first
place we don’t know how to fix it means
that we don’t know how to develop better
agents and that’s why steadily over the
past few decades the research community
has just lost interest in bettering and
optimizing these agents okay so we said
let’s start there let’s go and optimize
our probes to be able to measure
serotonin and let’s just ask is there
indifferent during depression or not so
we did this it took us a long time but
we made these measurements in rodent
rodent models we asked is serotonin
different in a depressed model versus a
non depressed model and we found that it
was actually we were surprised we found
very robustly in models of depression
that the serotonin levels were lower so
we have for the first time in decades
prove this hypothesis
still doesn’t tell us why the SSRIs are
not effective clinically because like I
said they’re tasked with increasing the
serotonin levels so the next experiment
that we did was to administer the SSRI
during depression and during the control
arm situation in the control situation
where there is no depression the SSRIs
very quickly and rapidly increased the
serotonin levels so far so good we would
expect that but this was not the case
during depression during depression the
SSRIs were much much less effective at
increasing the serotonin levels that’s
interesting so we asked why during
depression serotonin levels are low when
the SSRIs are much much less effective
at increasing the serotonin levels so I
want you to follow me on a train of
there’s a big trend and psychiatric
disease research this is a trend that
involves a phenomenon called neuro
inflammation neuro inflammation is a
general term that is used to describe
our brains immune reaction to something
whether it’s a physician or it’s some
chronic disease and actually it’s a
little more profound than that neuro
inflammation occurs when there is a
bodily inflammation so if our bodies are
fighting something our brains are
fighting something too so our body’s
immune reactions are linked to our
brains immune reactions in recent years
researchers have found a very close link
between neuro inflammation and
psychiatric disorders in particular
depression
there’s no depression without neuro
inflammation there’s no neuro
inflammation without depression it’s a
little bit of a chicken the next story I
thought what is neuro inflammation doing
to these neurotransmitters in our brain
and nobody knows very much about that we
do know something about bodily
inflammation when the body is fighting
something there are higher levels of a
molecule called histamine in our bodies
histamine if you have allergies or if
you’re fighting something you’re sick
the levels of histamine are higher this
was interesting to me because for a long
time people have thought that histamine
in the brain drives down serotonin
levels so I wanted to know during neuro
inflammation are the levels of histamine
in the brain higher so we went back to
the drawing board and we engineered our
probes to be able to simultaneously
measure serotonin and histamine we did
this and it turns out very robustly
drawing all of the depression models
that we’ve looked at there’s more
histamine in the rain and as a
consequence there’s less serotonin
alright so we know serotonin levels are
lower during inflammation and depression
we know that that’s because the
histamine levels are higher but we still
don’t know why these SSRIs I’m not very
effective it turns out when they were
developing the SSRIs they didn’t know
much about histamine no one was thinking
about histamine so they made them
selective was regard to the things that
we knew about things like dopamine and
norepinephrine see but because we
weren’t thinking about histamine we
didn’t care too
look at their effects on histamine so
this is what we did we looked at what
these agents are doing to the brain has
to mean and guess what
all of them are also increasing the
histamine levels in the brain all right
so let me put this together for you the
issue at hand is that serotonin is lower
during depression one of the primary
reasons is that histamine is higher
because our brains are undergoing neuro
inflammation so we have a seesaw
scenario here
our primary bid to increase the levels
of serotonin with the SSRIs is also
increasing the levels of histamine which
is driving the serotonin levels back
down so you get no net effect and all of
this is dependent on our immune systems
– different from yours it’s different
from yours so this speaks volumes to me
in terms of the huge clinical
variability in their response because
all of our immune systems are different
alright so this is really exciting we
have for the first time I believe
figured out chemical markers of
depression histamine and serotonin and
how can we now think about a treatment
strategy okay we started to think of
agents that would mitigate the effects
of histamine on serotonin I know what
you’re thinking some of you are thinking
antihistamine is correct unfortunately
that won’t work for us because
antihistamines are designed to mitigate
histamines effects on histamine so we
need to define an agent that would help
us with a scenario and we did we found
an agent that was able to globally lower
the levels of histamine during
inflammation when we co administered
that agent with the SSRI during
depression we were able to get the
serotonin levels right back up to the
control values and this was associated
with a diminishment and the depression
symptoms so this is really exciting
we’ve got the means for a diagnosis
we’ve got the means for treatment but
the experiments that I’ve described to
you happen in well controlled rodent
models in our lab what does it mean for
you what does it mean for you when you
make that appointment to get a diagnosis
I still can’t open up your brain and put
a pearl
so here’s what I’m thinking let me
introduce you at this point to my best
friend my best man this ginger ginger
helped me with this ginger is the best
dog in the world best dog in the world
anybody that’s ever met ginger will
agree best dog hands-down I’m not the
only one that says that about my dog if
you have a dog you probably think the
same about your dog we as humans have a
very special relationship with our dogs
from variety of reasons dogs are
fascinating for me what’s really
fascinating about a dog is the dogs
sense of smell I’m a sensor person
there’s no more exquisite sensor than
that dogs olfactory system other animals
have exquisite olfactory systems but
what makes dogs so special is that
they’re smart enough to be able to
attribute sense to our own moods when
I’m sad and you’ll come sit with me and
the smartest of dogs can be trained to
actually sniff out specific markers of
our moods and correlate them see to PTSD
or anxiety attacks and this saved lives
they’re smelling our moods they’re
smelling something outside of the brain
that’s telling them how we feel
unfortunately ginger can’t tell me what
that is
but I thought about this for many years
what can we use outside of our body to
give us an indication of what’s
happening in our brains I tried a bunch
of different things and I’m really
excited to focus in on this idea of stem
cells stem cells are cells that we can
take from our body you can take them
from the skin they contain all of the
genetic information that if exposed to
the right combination of chemicals and
growth factors they can be turned to any
type of cells in our bodies we have
colleagues that have figured out how to
take human stem cells skin cells and
turn them into serotonin neurons so we
did this we grew serotonin neurons in
the petri dish and my question was if I
put my probe in there can I measure
serotonin in the same way that I measure
in the brain and the answer is yes these
cells release serotonin the reuptake it
very much like the diagram that I showed
you so my next question is are these
cells now reflecting what’s going on in
the brain
so we’re doing a large-scale study with
while comparing depressed versus non
depressed and so far so good
it looks like all avenues are pointing
to yes so this is really exciting to us
now because for the first time we have
this idea of taking something peripheral
outside of the brain to give us
information about the brain no need to
open up your braid and put a probe in
there all you have to do is take a skin
swab we grow those selves turn them into
serotonin neurons make the chemical
measurement make a diagnosis depending
on the levels of serotonin and histamine
we could come up with a personalized
therapy strategy for youth and that
would be different than it would be for
you and that would be different than it
would be for you you imagine now making
that appointment going to the doctor the
ultimate goal would be to have some sort
of microchip that the doctors and the
practitioners could use in-house to grow
your cells and maybe get an answer
within hours or days and that’s a
definitive diagnosis that takes the
opinions out of that diagnosis much more
streamlining the treatment strategies
taking the opinions out of diagnosis
will take out the taboos and the stigma
that’s a definitive diagnosis having a
definitive treatment strategy will allow
us to treat psychiatric diseases with
the same clinical precision that we
treat bodily diseases allowing us to
take an on shameful view towards
depression as we do say to diabetes thank you
[Applause]
imagine you start to feel sick maybe
you’re a bit thirsty more than usual
very fatigued using the bathroom a lot
more than usual
perhaps you start getting blurry vision
you suspect it might be diabetes so you
make an appointment with your doctor in
hopes of getting a diagnosis and some
treatment now imagine at this
appointment the very best your doctor
could do is ask you some questions about
your symptoms no blood tests no panels
and then offer you an opinion on your
diagnosis well it may be diabetes and
then prescribe you an angel that
wouldn’t work for the majority of
patients who take it at a dose that
you’d likely have to adjust through
trial and error and repeated visits and
this particular agent will likely make
you feel a lot worse for several weeks
before it starts to make you feel better
sounds pretty unbelievable right in this
day and age of technological advancement
you don’t want your diabetes to be
somebody’s opinion you want a definitive
diagnosis based on a blood test and the
measurement of some chemicals in that
blood and then a treatment strategy
that’s aimed to normalize the levels of
those chemicals and make you feel better
unfortunately as unreal and outdated as
that sounds if you were to make an
appointment to have a mental illness
diagnosis that’s precisely what would
happen mental illnesses are in many ways
much more devastating than bodily
illnesses eight million people die a
year from mental illnesses the W Health
Organization has stated that mental
illnesses such as depression are the
leading cause of disability worldwide
and pose the largest economic burden one
in five Americans is prescribed
antidepressants let’s think about that
for a second that’s a phenomenal number
of people that’s a huge amount of people
and antidepressants don’t work for the
majority of patients who take them and
for reasons that I’m going to get to a
little bit later I’ll outline the fact
that the research community has lost
interest in recent years in developing
better and more improved Lant I present
the present therapies mental illnesses
unlike bodily illnesses are fraught with
shame and taboos and stigma so what’s
the difference between mental illnesses
and diseases of the body what’s the
difference between say diabetes and
depression well the primary difference
is that we understand diseases of the
body much much better than we understand
diseases of the brain let’s talk about
diabetes we know the chemicals that will
mark diabetes amongst others these are
things like glucose and insulin we may
take a blood sample we can measure
glucose and insulin and because we know
what’s wrong we can make a diagnosis
based on those chemicals and we can
develop drugs to target glucose and
insulin and get them back to normal and
make you feel better
unfortunately that’s not the case for in
psychiatric diseases why is that there’s
a strict separation between the body and
the brain it’s called the blood-brain
barrier it exists for a really good
reason it exists to strictly control the
inflow and outflow of chemicals out of
our brains into our brains protects us
from things say like bacteria and
viruses but what it means is that if we
take blood their levels of chemicals in
our blood do not reflect the levels of
chemicals in our brain so to ask
questions of the brain then you would
think perhaps we should take a sample of
the brain while taking a blood sample
what no one likes to do it but it’s a
relatively simple and non disturbing
thing we can’t really think about
opening up someone’s skull and taking a
sample this is potentially devastating
we can’t do that
plus if you think about it you think the
chemicals that we would be looking for
that would likely mark an illness these
are chemicals I’m gonna call
neurotransmitters neurotransmitters are
chemical transmitters that take messages
from one brain cell to another from one
neuron to another they do this through
the tiniest of Junction
that Junction is called a synapse it’s
so small it’s about a thousandth of a
human hair the thousandth of diameter of
a human hair and they do it real
dynamically very very fast they move
from one cell to another within a second
so taking a sample like you wouldn’t
tell us very much about the
functionality of the system to do that
we want to look in on it while it’s
working without disturbing it how do we
do it well over the past decade or so my
research program has been to take a
technical approach to this problem we’ve
developed ultra ultra tiny probes made
out of carbon they’re not a thousandth
of a human hair perhaps our hundredth of
a human hair but they’re so small that
we can directly implant them into tissue
and measure these neurotransmitters as
they go about their business without
disturbing the system so that’s exciting
we have some technology now that we can
use to perhaps ask some questions of the
brain so when it comes to psychiatric
diseases where do we start let’s just
focus on depression what should we
measure well back in the late 70s there
was something called the mono amine
hypothesis of depression and here’s how
it went the idea was that people that
were experiencing depression the levels
of certain of these neurotransmitters in
particular neurotransmitter called
serotonin are lower between the cells
and someone who is not experiencing
depression now mind you this was a
hypothesis with no real way to test it
because the technology wasn’t available
but the hypothesis precipitated the
development of the modern-day
antidepressants that we know as SSRIs
the selective serotonin reuptake
inhibitors the idea is that these drugs
will block a key protein that’s tasked
with clearing serotonin from from the
extracellular space and the idea is that
the serotonin levels will go up and
alleviate depression symptoms the theory
precipitated the development the first
of a type of the first of their type of
these agents was Prozac and since the
late 70s the agents haven’t changed very
much like I said they don’t work for the
majority of patients who take them about
70% of patients do not experience
clinical relief and there
a lot of unwanted side-effects so there
are issues here the hypothesis has been
around there’s been no real way to test
it so till now we still don’t know where
the serotonin is different during
depression or not no one really knows
how these SSRIs work so the fact that we
don’t know what’s wrong in the first
place we don’t know how to fix it means
that we don’t know how to develop better
agents and that’s why steadily over the
past few decades the research community
has just lost interest in bettering and
optimizing these agents okay so we said
let’s start there let’s go and optimize
our probes to be able to measure
serotonin and let’s just ask is there
indifferent during depression or not so
we did this it took us a long time but
we made these measurements in rodent
rodent models we asked is serotonin
different in a depressed model versus a
non depressed model and we found that it
was actually we were surprised we found
very robustly in models of depression
that the serotonin levels were lower so
we have for the first time in decades
prove this hypothesis
still doesn’t tell us why the SSRIs are
not effective clinically because like I
said they’re tasked with increasing the
serotonin levels so the next experiment
that we did was to administer the SSRI
during depression and during the control
arm situation in the control situation
where there is no depression the SSRIs
very quickly and rapidly increased the
serotonin levels so far so good we would
expect that but this was not the case
during depression during depression the
SSRIs were much much less effective at
increasing the serotonin levels that’s
interesting so we asked why during
depression serotonin levels are low when
the SSRIs are much much less effective
at increasing the serotonin levels so I
want you to follow me on a train of
there’s a big trend and psychiatric
disease research this is a trend that
involves a phenomenon called neuro
inflammation neuro inflammation is a
general term that is used to describe
our brains immune reaction to something
whether it’s a physician or it’s some
chronic disease and actually it’s a
little more profound than that neuro
inflammation occurs when there is a
bodily inflammation so if our bodies are
fighting something our brains are
fighting something too so our body’s
immune reactions are linked to our
brains immune reactions in recent years
researchers have found a very close link
between neuro inflammation and
psychiatric disorders in particular
depression
there’s no depression without neuro
inflammation there’s no neuro
inflammation without depression it’s a
little bit of a chicken the next story I
thought what is neuro inflammation doing
to these neurotransmitters in our brain
and nobody knows very much about that we
do know something about bodily
inflammation when the body is fighting
something there are higher levels of a
molecule called histamine in our bodies
histamine if you have allergies or if
you’re fighting something you’re sick
the levels of histamine are higher this
was interesting to me because for a long
time people have thought that histamine
in the brain drives down serotonin
levels so I wanted to know during neuro
inflammation are the levels of histamine
in the brain higher so we went back to
the drawing board and we engineered our
probes to be able to simultaneously
measure serotonin and histamine we did
this and it turns out very robustly
drawing all of the depression models
that we’ve looked at there’s more
histamine in the rain and as a
consequence there’s less serotonin
alright so we know serotonin levels are
lower during inflammation and depression
we know that that’s because the
histamine levels are higher but we still
don’t know why these SSRIs I’m not very
effective it turns out when they were
developing the SSRIs they didn’t know
much about histamine no one was thinking
about histamine so they made them
selective was regard to the things that
we knew about things like dopamine and
norepinephrine see but because we
weren’t thinking about histamine we
didn’t care too
look at their effects on histamine so
this is what we did we looked at what
these agents are doing to the brain has
to mean and guess what
all of them are also increasing the
histamine levels in the brain all right
so let me put this together for you the
issue at hand is that serotonin is lower
during depression one of the primary
reasons is that histamine is higher
because our brains are undergoing neuro
inflammation so we have a seesaw
scenario here
our primary bid to increase the levels
of serotonin with the SSRIs is also
increasing the levels of histamine which
is driving the serotonin levels back
down so you get no net effect and all of
this is dependent on our immune systems
– different from yours it’s different
from yours so this speaks volumes to me
in terms of the huge clinical
variability in their response because
all of our immune systems are different
alright so this is really exciting we
have for the first time I believe
figured out chemical markers of
depression histamine and serotonin and
how can we now think about a treatment
strategy okay we started to think of
agents that would mitigate the effects
of histamine on serotonin I know what
you’re thinking some of you are thinking
antihistamine is correct unfortunately
that won’t work for us because
antihistamines are designed to mitigate
histamines effects on histamine so we
need to define an agent that would help
us with a scenario and we did we found
an agent that was able to globally lower
the levels of histamine during
inflammation when we co administered
that agent with the SSRI during
depression we were able to get the
serotonin levels right back up to the
control values and this was associated
with a diminishment and the depression
symptoms so this is really exciting
we’ve got the means for a diagnosis
we’ve got the means for treatment but
the experiments that I’ve described to
you happen in well controlled rodent
models in our lab what does it mean for
you what does it mean for you when you
make that appointment to get a diagnosis
I still can’t open up your brain and put
a pearl
so here’s what I’m thinking let me
introduce you at this point to my best
friend my best man this ginger ginger
helped me with this ginger is the best
dog in the world best dog in the world
anybody that’s ever met ginger will
agree best dog hands-down I’m not the
only one that says that about my dog if
you have a dog you probably think the
same about your dog we as humans have a
very special relationship with our dogs
from variety of reasons dogs are
fascinating for me what’s really
fascinating about a dog is the dogs
sense of smell I’m a sensor person
there’s no more exquisite sensor than
that dogs olfactory system other animals
have exquisite olfactory systems but
what makes dogs so special is that
they’re smart enough to be able to
attribute sense to our own moods when
I’m sad and you’ll come sit with me and
the smartest of dogs can be trained to
actually sniff out specific markers of
our moods and correlate them see to PTSD
or anxiety attacks and this saved lives
they’re smelling our moods they’re
smelling something outside of the brain
that’s telling them how we feel
unfortunately ginger can’t tell me what
that is
but I thought about this for many years
what can we use outside of our body to
give us an indication of what’s
happening in our brains I tried a bunch
of different things and I’m really
excited to focus in on this idea of stem
cells stem cells are cells that we can
take from our body you can take them
from the skin they contain all of the
genetic information that if exposed to
the right combination of chemicals and
growth factors they can be turned to any
type of cells in our bodies we have
colleagues that have figured out how to
take human stem cells skin cells and
turn them into serotonin neurons so we
did this we grew serotonin neurons in
the petri dish and my question was if I
put my probe in there can I measure
serotonin in the same way that I measure
in the brain and the answer is yes these
cells release serotonin the reuptake it
very much like the diagram that I showed
you so my next question is are these
cells now reflecting what’s going on in
the brain
so we’re doing a large-scale study with
while comparing depressed versus non
depressed and so far so good
it looks like all avenues are pointing
to yes so this is really exciting to us
now because for the first time we have
this idea of taking something peripheral
outside of the brain to give us
information about the brain no need to
open up your braid and put a probe in
there all you have to do is take a skin
swab we grow those selves turn them into
serotonin neurons make the chemical
measurement make a diagnosis depending
on the levels of serotonin and histamine
we could come up with a personalized
therapy strategy for youth and that
would be different than it would be for
you and that would be different than it
would be for you you imagine now making
that appointment going to the doctor the
ultimate goal would be to have some sort
of microchip that the doctors and the
practitioners could use in-house to grow
your cells and maybe get an answer
within hours or days and that’s a
definitive diagnosis that takes the
opinions out of that diagnosis much more
streamlining the treatment strategies
taking the opinions out of diagnosis
will take out the taboos and the stigma
that’s a definitive diagnosis having a
definitive treatment strategy will allow
us to treat psychiatric diseases with
the same clinical precision that we
treat bodily diseases allowing us to
take an on shameful view towards
depression as we do say to diabetes thank you
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