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