Deciphering the Alzheimers Enigma Using Technology
[Music]
hi
i’m a neuro engineer meaning i’m making
new tools
to study the brain so you see this guy
in the
black and white picture this is abraham
siton
this fine chap was a borderline
communist god forbid
took part in world war ii and gave me
these magnificent eyebrows
since it was my grandfather now remember
it was back in 2000 my mom calls me and
she says
grandpa was diagnosed with alzheimer’s
disease
so i spoke with his doctors and asked
will he be okay what is the prognosis
and he said it was pretty grim and then
i asked
what about a cure and he said not within
the next
hundred years so i said challenge
accepted
and went and learned more about brain
disease i studied neuroscience
and later engineering and joined mit to
create tools to study the brain
now what i want to tell you today is
that my grandpa’s fate
is becoming more and more common that it
will become a
problem at the magnitude of climate
change or pandemics
and that we as scientists have failed
in providing an understanding of
alzheimer’s disease
we failed miserably but the upside
is that the problem can be solved by
creating the right technologies
to study alzheimer’s in other words
today we’ll discuss why we fail to solve
alzheimer’s disease
and how we reverse it using technology
let me explain today i’ll talk about
one how big a deal is alzheimer’s
disease
two why we are failing in understanding
alzheimer’s disease
and three how technology can help in
understanding
and curing alzheimer’s disease i’ll
describe three technologies
or tools as i call them and one
experiment
we can perform with these tools
first let’s talk a bit about alzheimer’s
well alzheimer’s disease is a dementia a
general term
for loss of cognitive function language
skills
memory and problem-solving abilities
alzheimer’s disease is also a
neurodegenerative disease meaning
cells in the brain are degenerating they
are simply dying
but is it a wide global issue
to answer this question let’s focus on
the top 10 leading causes of death
worldwide take a look at the year 2000
the top spot was occupied by
cardiovascular diseases
followed by cancers the number 10 cause
of death was dementia
let’s fast forward to 2017 dementia rose
from the 10th spot
to the fifth this is a killer on the
rise
by 2050 110 million people
will be affected by dementia this means
that you
or a loved one are very likely to cross
paths with the disease it is also a
substantial financial burden
alzheimer’s disease and other dementias
cost approximately
one percent of the world’s gdp now
just like with my grandpa being
diagnosed with a neurodegenerative
disease
usually has a grim outlook but what
makes alzheimer’s so deadly
simply put when it comes to
neurodegenerative diseases
we do not know their causes for the vast
majority of them
why have we failed well there are three
main reasons why we don’t know the cause
of alzheimer’s disease
and they are all related to the way we
study the disease
here are the three plagues that prevent
us from understanding and curing
alzheimer’s
the first plague is the genetic bias
alzheimer’s disease is not a genetic
disease
meaning we do not transmit the disease
to our children
through our genes however one in
200 or 100 alzheimer’s cases
comes from a genetic cause small
mistakes in a person’s dna
will cause them to develop this familial
alzheimer’s disease
despite the fact that alzheimer’s is not
genetic
the vast majority of research is done in
mice
wherein these small mistakes are
incorporated
into the mouse dna and scientists
study the ensuing effects so we are
studying a
non-genetic disease with genetic tools
the second plague is searching for a
cure
instead of a cause what do i mean
there is a big push in pharma and in
academia
to look for a cure but how can we look
for a cure
when we have no idea about the cause
this is the equivalent of shooting darts
without knowing where the bullseye is
you can hit it but it’s very unlikely
the third plague is seeing symptoms
as causes for this third plague
allow me to dive a bit into the biology
of alzheimer’s
the brains of people who died of
alzheimer’s disease have two
major lesions or pathologies one is
mostly mostly outside of cells
called senile plaques that are made of a
protein called
beta amyloid protein and the other is
mostly
mostly inside cells which is an abnormal
form of a protein
called tau that forms tangles inside the
cells
the alzheimer’s disease community found
these pathologies
and has been brawling for three decades
about the question
which of these two proteins is causative
in alzheimer’s disease
but in fact we still do not have a clear
answer
how do we know because most of the 400
failed clinical trials against
alzheimer’s disease
aim at these two pathologies i’m not
saying that they are
not the cause i’m saying that we need a
way to answer if they are the cause
or not now we get to the third and
interesting part
so how do we deal with these plagues
here’s what we do we create tools that
aim at
non-genetic alzheimer’s disease focus
on a cause and not just a cure and look
beyond the old ideas about tau
and a beta so what technologies will
help us understanding how alzheimer’s
disease develops and manifests
well simply put we need to go to the
beginning
we need technologies that can study the
seeding
cellular and molecular events that lead
to alzheimer’s disease
how what kind of technologies well
let’s fantasize since they do not fully
exist
let’s say that we want to study
alzheimer’s disease
a common way is to look into the brains
of mice
rather than humans now mice do not get
alzheimer’s
and also have proven to be a terrible
predictor
for the success of candidate drugs we
should and will replace
mice but this is a subject of a
different talk
so let’s use mice as a genetic term for
a platform
here are the tools the first tool is
readout of cell death we know that cells
die
in neurodegenerative diseases so the
question we
really want to ask is what kills them
for that it would be useful to watch
them as they die
in real time this way if we hypothesize
that something causes alzheimer’s
disease
say chocolate milk we can expose mice to
chocolate milk
and see whether it kills cells but how
do we see anything in the brain
a common trick is to make a glass window
looking
into the mouse brain and use a
microscope to image
and peer into the brain’s biology but
how can we see
cell death here comes our shiny new tool
these are some of the brain’s cells
called neurons
these neurons have a cell body and
elongated processes
we can fill these neurons with a
specific fluorescent dye
when one of these cells is dying they
become more fluorescent
they blink so
we give the mice some chocolate milk we
peer
into the brains using a microscope and
we see that cells are dying in real time
this will mean that chocolate milk alas
is causing
neural degeneration the second type of
tool
is actuating alzheimer’s pathology
so just looking at cells dying can tell
us everything about alzheimer’s
since there are many diseases during
which cells die
can we study something that is at least
somewhat unique to alzheimer’s
well remember that senile plaques exist
outside of cells and top pathology forms
tangles
inside of neurons so how do we figure
out if
tau or beta amyloid are relevant to
alzheimer’s disease
we gain control over them we create them
within the brain at the time an area of
interest
and see whether they are toxic to
neurons causing them
the so-called degeneration so how do we
gain this control over them
a unique way is to use molecular light
switches
what do i mean we can fill neurons
with molecules that are sensitive to
light once the neuron is hit by light
it produces the pathology in this case a
beta plaque
made of beta-amyloid protein and then we
can ask
did beta-amyloid protein kill the cells
expressing it
did it kill cells in its vicinity did it
change the connections
between neurons and many other questions
relevant to the disease
the third type of tool is reading out
alzheimer’s pathology and how do we
monitor these
pathologies in the live brain well right
now they’re invisible to our microscope
but we want to see them right just like
we made these fluorescent indicators for
cell death
we can make fluorescent indicators for
the pathologies
showing them forming in real time so
what crucial question can we now ask
with the tools i just described
we can ask does a pathology kill
neurons and change behavior here is the
million dollar experiment by shining
light
we create a pathology using our light
switches let’s say tau pathology
we image the ensuing formation of this
type pathology in the live brain
and we see if it causes cells to die
using
cell viability indicators
finally we test if this experimental
manipulation
changed animal behavior and produced
alzheimer’s like symptoms such as
learning and memory impairment
did the mouse start forgetting where it
left the car keys
basically i’m proposing counter disease
engineering
solving all neurodegenerative diseases
by creating the tools to study them the
tools can come from many disciplines of
engineering
bioengineering chemical engineering
genetic engineering
electrical engineering to name a few
we can create a plethora of tools we
should build light switches for cell
pathology
we should engineer readout strategies
for cell viability
or death we should create tiny devices
that monitor
cellular health and we should find ways
to study alzheimer’s disease
non-invasively
in humans rather than mice
and the list goes on i neglected a lot
here
but the key to solving diseases is
engineering tools
we are as smart as the technologies we
make
or not so how does creating the tools
relate to you
how does it relate to us first
i think we should all realize that
alzheimer’s is here to stay
unless we do anything about it it is
increasingly becoming
a leading cause of death let’s treat
this looming threat
now perhaps a bit better than we treated
climate change or pandemics if you’re a
policy maker
or a member of the national institute of
health
i think it’s time for a diseased brain
initiative
how about a war on alzheimer’s
if you’re a part of a foundation or a
philanthropy group
please also fund alternative hypothesis
not just the well-visited path please
find the riskier stuff
since the answer might be there too if
you’re a scientist
let’s do this we live in an exciting
time where we have the biological
engineering
magic wands at our fingertips and we
just need to get going
and create the tools go wild but
remember the goal
if you belong to the pharma industry
perhaps search
also for a cause not just for a cure
maybe the crew will present itself once
we know the causes of
alzheimer’s parkinson’s als cte and many
other diseases
we will be able to treat and even
reverse them
at a snippet of the time in a fraction
of the cost it took before
i’m talking millions of dollars rather
than trillions
10 years rather than a century
so don’t believe those who tell you that
understanding dementia cannot be
achieved in your lifetime
we can solve this we only need to get to
work
thank you