if you have looked at the newspaper at
the newspaper recently you’re fully
aware of the problem I want to discuss
with you today I’ve put a few headlines
in this slide behind me but the main
message is all the same drugs and
especially drugs for rare diseases are
becoming increasingly expensive and in
many cases even literally unaffordable
and pharmaceutical companies are blamed
healthcare insurance companies are
blamed and politicians as they tend to
do they blame each other but there’s one
thing really clear and it’s that the
development costs for these drugs for
new drugs have increased dramatically in
the last decades and the reason behind
this is actually something you’re also
fully aware of and even if you haven’t
read a newspaper in the last ten years
because what our drugs usually tested on
animals
yes exactly thank you so it’s we have
really simple models we call them in
vitro models then we test on animals and
when these preclinical models as we call
them are done and they’re proven to be
safe we go and test drugs on humans in
the clinical trials now in these
preclinical trials pharmaceutical
companies have invested millions of
dollars sometimes even billions of
dollars and years and years of of
research but despite all those
investments we still see that as soon as
we test them in humans nine out of ten
drugs fail directly and of course that
one drug that does make it through the
markets has to compensate for the cost
that has been generated by all the drugs
that are lost along the way now why are
these preclinical models so inaccurate
why can they not predict what’s
happening in a human body well here’s
why and this is going to shock you but
animals are not the same as humans now
this is a conclusion that my
four-year-old niece will be able to draw
that’s true but it’s really important if
we look more closely at the different
species for example at the heart and
heart is of course really important if
we want to determine whether a drug is
safe to give to a patient if we look at
the heart of a mouse and a human
the first thing we measure is the beat
rate now of a mouse it goes about 500
beats per minute and the human normally
around 60 or 80 I think mine is a little
bit higher now but okay and that’s not
the biggest problem actually the biggest
problem is the biology that is
underlying this difference in beat rate
and that’s the electrical activity of
the heart and you all know this
electrical activity from the hospital
right it’s the ECG it goes
beep-beep-beep if everything’s fine and
if everything goes south it goes beep
and then everybody comes well you know
this but this electrical activity is the
trigger of your heart now you see that
the trigger in the mouse and in the
human is completely different the shape
and the timing is different and this is
because the proteins and molecules that
work together to generate this
electrical activity they are completely
different than the mouse in any human so
if we have a drug and many drugs
actually interact with these proteins
and these molecules if we have a drug
that we give to the mouse and we don’t
see any effect it doesn’t necessarily
mean that there’s no effect on the
electrical activity of the human so this
makes it really tricky to determine
whether something is safe to give to a
patient based on the results of a mouse
so you might think okay well then we’re
gonna test everything on humans well
apart from all the ethical issues I’ll
give you another life lesson humans are
not the same as humans either well at
least in some cases for example think
about a patient that has cancer or two
patients that have cancer they have the
same type of cancer and they give they
are given the same chemotherapy and we
know that some patients get well while
others do not
they don’t see an effect at all now this
difference is in part because the body
responds differently to the same disease
or everybody every individual body
responds differently to the same disease
or a same drug now that’s why we want to
test something not on just any person on
any human being but we want to test
something specifically on you and in
some cases this was already being done
for example if you think you have an
allergy you go to the doctor and he
exposes your skin to different kind of
potential allergens now whatever
whichever one shows a breath is the easy
one as
causing the allergy but for example for
the heart you already notice it’s my
favorite organ this is impossible
we cannot just expose a part of our
heart to some kind of drug or some kind
of therapy we can also not just remove a
part out of it and put it in addition
test our drugs there because if we
remove something of our heart it doesn’t
grow back easily and that’s why in the
lab where I work we are trying to
recreate the piece of your heart in a
dish from scratch well not entirely from
scratch we try to do this from stem
cells and you all know stem cells there
in our body and you might know them from
stem-cell therapy and then usually they
are removed from your bone marrow but
you also have them in your skin and you
also have them in your guts and we call
them adult stem cells and we call an
adult not because they are in your adult
body but because they’re already
directed to become a certain type of
tissue so stem cells in the skin will
only become skin cells stem cells in the
gut will only become gut cells however
when you were young and now young is a
kind of an understatement because was
when you were an embryo you actually
consisted of a bowl let’s say of
different kind of stem cells they are
called pluripotent stem cells they can
become everything of the human body in
fact they have you have become
everything out of these stem cells
unfortunately we lose these cells during
the development now in 2006 there was a
smart scientist Yoshi
Shinya Yamanaka have to say correctly
and he won the Nobel Prize for this and
for this discovery where he realized we
could remove cells from our adult body
then put them in a dish in the lab in a
petri dish and then genetically
reprogram them to become pluripotent
stem cells again and these cells can now
again become everything in the human
body and we use those cells these kind
of cells in our lab to make heart cells
and we do this by following sort of a
nature inspired cooking recipe so bay
we have these cells in a dish and we add
hormones and growth factors just as
these cells would experience when
they’re in the human body during the
development of the heart and after two
weeks of adding these hormones growth
factors and removing them again we look
under the microscope and we see this
beating and they’re really slowly
beating here but there and normally it’s
sort of similar pace is the human
because they’re beating human heart
cells in a dish of whoever we made them
of and you have to imagine what this
means what we can do with this for
example if we have two patients and one
of them has a mutation in its DNA that
prolongs the electrical activity the ECG
what we already talked about in the
hospital this prolongation is
potentially dangerous is if we give a
drug that prolongs the electrical
activity even more so what we can do now
is take a piece of skin or urine or
blood from these patients extract the
cells reprogram those cells into
pluripotent stem cells and then
differentiate them towards our heart
cells and what we then get and what we
can measure and colleagues of mine in my
lab have done this we find the same
electrical activity prolongation and
electrical activity in those cells as we
see in the patients and now we can use
this to test drugs and to see if we can
either rescue the phenotype or see which
drugs are tolerated by the patients now
this might be the right time to
introduce a big disclaimer because about
all of this biology
don’t trust me I’m an engineer actually
I studied electrical engineering at the
Technical University of Delft and I was
trained to build computer chips like the
ones in your smartphone now you might
ask how do you go from building computer
chips towards growing cardio the cardiac
cells that’s a good question and you
might also ask why well the why is
actually simple
I’m gonna show you this movie again
because I think this is absolutely
incredible
these cells are more ingenious than
anything we’ve ever ever engineered but
then the how how does it work what does
an engineer do in a developmental
biology lab well to be honest when I
started in that lab I didn’t really have
a clear idea as well but it turns out
that if we combine the biological
knowledge with the technological
knowledge that we can actually make
really complex tools like the one showed
here and I cannot go into all the
technical details of the system but what
we can do with it is measure the three
most fundamental parameters of the heart
simultaneously and this is the
electrical activity that you all know by
now and the contraction which is of
course the end goal of the cells and
finally the calcium and the calcium is
necessary for cells to contract now
these kind of systems we we can make
with this combination of technology and
biology and what we do is we have the
cells in a sort of a petri dish well
actually is a sort of plate with a lot
of petri dishes we grow ourselves there
then we add an optical chemical dye
inside and this optical chemical dye is
triggered by the leds on the other side
and then with the high-speed camera
that’s attached to the microscope we can
make a really nice recording with a high
temporal resolution so we can get a
really accurate measurement of what is
going on there and I’ll show you a movie
how that looks like in a bit but first
I’ll show you what the setup looks like
so it’s kind of dark you see a lot of
wires but if you don’t believe it really
takes an engineer to build this I made a
kind of an enlargement of a certain area
and you clearly see duct tape and dyrus
I can tell you it’s state of the art
engineering but what’s really cool is if
we is when we look through the
microscope and what I’m going to show
you is a movie of the cells that are
labels that are loaded with this calcium
sensor and every time the cells beeped
you see that the calcium sensor
increases in activity so these are again
human heart cells in a dish and on the
right side you see a graph and this
tracks the intensity of the cells this
tracks how many calcium is in it cells
and with this kind of tools we can
actually test what a drug does so there
are many drugs that have a negative
effect on the calcium in the cell if we
would add this this to it as well to
this piece of cells we will see that the
activity drops and this is exactly the
tool that we can use to test new drugs
however we still need to check whether
it works with the old drugs
that’s our validation set and this is
exactly what we’ve done we’ve worked
together with a pharmaceutical company
and they gave us ten drugs we didn’t
know which one was which and we had to
test them one by one using your system
now after a while we came back and seven
out of ten we had correct if it was
exactly what they and we predicted
exactly what they found in humans two
out of ten were completely wrong
and one well I think we were right they
think we’re wrong but we’ll settle in
the middle so it’s 75% correct I think
this is already really good but we want
to get to this hundred percent we use
human cells why isn’t it hundred percent
yet there are two reasons mainly one is
because we’re only looking at the heart
and it’s not an complex interplay of the
organs as we find in the human body and
the second one is that the cells are
still bit immature like you would find
in a newborn baby for example and we can
see this if we look at the electrical
activity again so the cells are in the
middle that we make and you can see this
electrical activity resembles the adult
electrical activity way more but it’s
not as good yet yet as the adult
compared to the mouse but it’s not as
good as the adult just yet the timing
and the shape is still a little bit off
and one of the reasons why it’s maybe a
little bit off is because the cells
don’t feel at home they’re in this petri
dish it’s
ridges they don’t like it in the heart
they are in his soft environment exactly
a nicely aligned in one direction and
they work together so what we try to do
and again engineering seems to be to
assumes to be the way to offer a
solution we made a really flexible soft
substrate and made really tiny grooves
of 20 micrometers inside and then we
grew the cells on top of them and this
is what we see the cells are now aligned
in one direction and they work together
to pull this piece of rubber up and down
and we were did this together with
engineers from the Technical University
in Delft and they took it to a step
further and they built this hard on chip
design device you can see a
cross-section of the design in blue you
see the cells and here you see again in
brown the the grooves in the flexible
substrate in the soft substrate now
there are also electrodes built into
this substrate so you can actually
measure the electrical activity of the
cells while they are contracting and to
make it even feel more at home
for the cells we also make this air
chamber which we can inflate and then
the cells are stretched and strained
just like they would experience when
they’re in the heart now this is what
this is the device looks like in real
life and you can see it’s really small
and making it really small is important
because we have we only need to use a
really small amount of cells which is of
course makes it makes it a lot cheaper
now by making it cheaper and more
accurate this is the way it’s going to
change the development cost for drugs
completely now we make this hard on chip
device but other people are making lung
on chip and skin on chip and actually
this whole field is called organ on chip
and in the Netherlands there’s just an
initiative that started where a lot of
scientists all over the Netherlands work
together to build mainly three different
organs which are the brain the gut and
and the heart and the idea is to to make
these exactly as the heart on chip with
cells from patients and
integrates the measurement methods etc
etc but not only make those three
devices separately but then couple them
together using a blood flow in between
and when we can change the microbiome
for example in the gut and see how that
affects the brain so we try to make a
complete avatar of a human on a chip we
try to make a complete avatar of you on
a chip if we use your cells now when I
talk about this you understand that we
need a lot of multidisciplinary research
to get this going and it’s good to get
this research further and what people
usually show when they talk about such
multidisciplinary research is a
schematic like this so we have this stem
cell biology field and we have this chip
technology field and where they meet
roughly in the middle there’s this organ
on chip field for example but I think
that’s wrong I think that’s the wrong
way to show it I think it’s different I
think if we think about this it should
be that this buy of the stem cell
biology field and the chip technology
field are separated and if people go out
of their own fields and meet each other
halfway we find an even bigger field
than the previous fields which is called
in this case organ and chip and this
happens every time so for example we are
during my research and organ on chip we
developed this software to quantify the
contraction of the heart muscle cells in
a dish and we showed it to medical
doctors and they were they were so
enthusiastic that were actually trying
it out in patients now so basically
we’re combining this organ on chip field
with the clinical field and again
there’s a huge increase in horizon and
this can happen again and again and
again think about it if we would combine
these technologies technologies with
complex data analysis or maybe if we
have a brain on chip maybe we can couple
it to human psychology and every time
our horizon will get bigger and bigger
and bigger and that’s why I believe if
we step out of our own fields
and cross that border swords eat each
other
that the possibilities are infinite
thank you [Applause]
the newspaper recently you’re fully
aware of the problem I want to discuss
with you today I’ve put a few headlines
in this slide behind me but the main
message is all the same drugs and
especially drugs for rare diseases are
becoming increasingly expensive and in
many cases even literally unaffordable
and pharmaceutical companies are blamed
healthcare insurance companies are
blamed and politicians as they tend to
do they blame each other but there’s one
thing really clear and it’s that the
development costs for these drugs for
new drugs have increased dramatically in
the last decades and the reason behind
this is actually something you’re also
fully aware of and even if you haven’t
read a newspaper in the last ten years
because what our drugs usually tested on
animals
yes exactly thank you so it’s we have
really simple models we call them in
vitro models then we test on animals and
when these preclinical models as we call
them are done and they’re proven to be
safe we go and test drugs on humans in
the clinical trials now in these
preclinical trials pharmaceutical
companies have invested millions of
dollars sometimes even billions of
dollars and years and years of of
research but despite all those
investments we still see that as soon as
we test them in humans nine out of ten
drugs fail directly and of course that
one drug that does make it through the
markets has to compensate for the cost
that has been generated by all the drugs
that are lost along the way now why are
these preclinical models so inaccurate
why can they not predict what’s
happening in a human body well here’s
why and this is going to shock you but
animals are not the same as humans now
this is a conclusion that my
four-year-old niece will be able to draw
that’s true but it’s really important if
we look more closely at the different
species for example at the heart and
heart is of course really important if
we want to determine whether a drug is
safe to give to a patient if we look at
the heart of a mouse and a human
the first thing we measure is the beat
rate now of a mouse it goes about 500
beats per minute and the human normally
around 60 or 80 I think mine is a little
bit higher now but okay and that’s not
the biggest problem actually the biggest
problem is the biology that is
underlying this difference in beat rate
and that’s the electrical activity of
the heart and you all know this
electrical activity from the hospital
right it’s the ECG it goes
beep-beep-beep if everything’s fine and
if everything goes south it goes beep
and then everybody comes well you know
this but this electrical activity is the
trigger of your heart now you see that
the trigger in the mouse and in the
human is completely different the shape
and the timing is different and this is
because the proteins and molecules that
work together to generate this
electrical activity they are completely
different than the mouse in any human so
if we have a drug and many drugs
actually interact with these proteins
and these molecules if we have a drug
that we give to the mouse and we don’t
see any effect it doesn’t necessarily
mean that there’s no effect on the
electrical activity of the human so this
makes it really tricky to determine
whether something is safe to give to a
patient based on the results of a mouse
so you might think okay well then we’re
gonna test everything on humans well
apart from all the ethical issues I’ll
give you another life lesson humans are
not the same as humans either well at
least in some cases for example think
about a patient that has cancer or two
patients that have cancer they have the
same type of cancer and they give they
are given the same chemotherapy and we
know that some patients get well while
others do not
they don’t see an effect at all now this
difference is in part because the body
responds differently to the same disease
or everybody every individual body
responds differently to the same disease
or a same drug now that’s why we want to
test something not on just any person on
any human being but we want to test
something specifically on you and in
some cases this was already being done
for example if you think you have an
allergy you go to the doctor and he
exposes your skin to different kind of
potential allergens now whatever
whichever one shows a breath is the easy
one as
causing the allergy but for example for
the heart you already notice it’s my
favorite organ this is impossible
we cannot just expose a part of our
heart to some kind of drug or some kind
of therapy we can also not just remove a
part out of it and put it in addition
test our drugs there because if we
remove something of our heart it doesn’t
grow back easily and that’s why in the
lab where I work we are trying to
recreate the piece of your heart in a
dish from scratch well not entirely from
scratch we try to do this from stem
cells and you all know stem cells there
in our body and you might know them from
stem-cell therapy and then usually they
are removed from your bone marrow but
you also have them in your skin and you
also have them in your guts and we call
them adult stem cells and we call an
adult not because they are in your adult
body but because they’re already
directed to become a certain type of
tissue so stem cells in the skin will
only become skin cells stem cells in the
gut will only become gut cells however
when you were young and now young is a
kind of an understatement because was
when you were an embryo you actually
consisted of a bowl let’s say of
different kind of stem cells they are
called pluripotent stem cells they can
become everything of the human body in
fact they have you have become
everything out of these stem cells
unfortunately we lose these cells during
the development now in 2006 there was a
smart scientist Yoshi
Shinya Yamanaka have to say correctly
and he won the Nobel Prize for this and
for this discovery where he realized we
could remove cells from our adult body
then put them in a dish in the lab in a
petri dish and then genetically
reprogram them to become pluripotent
stem cells again and these cells can now
again become everything in the human
body and we use those cells these kind
of cells in our lab to make heart cells
and we do this by following sort of a
nature inspired cooking recipe so bay
we have these cells in a dish and we add
hormones and growth factors just as
these cells would experience when
they’re in the human body during the
development of the heart and after two
weeks of adding these hormones growth
factors and removing them again we look
under the microscope and we see this
beating and they’re really slowly
beating here but there and normally it’s
sort of similar pace is the human
because they’re beating human heart
cells in a dish of whoever we made them
of and you have to imagine what this
means what we can do with this for
example if we have two patients and one
of them has a mutation in its DNA that
prolongs the electrical activity the ECG
what we already talked about in the
hospital this prolongation is
potentially dangerous is if we give a
drug that prolongs the electrical
activity even more so what we can do now
is take a piece of skin or urine or
blood from these patients extract the
cells reprogram those cells into
pluripotent stem cells and then
differentiate them towards our heart
cells and what we then get and what we
can measure and colleagues of mine in my
lab have done this we find the same
electrical activity prolongation and
electrical activity in those cells as we
see in the patients and now we can use
this to test drugs and to see if we can
either rescue the phenotype or see which
drugs are tolerated by the patients now
this might be the right time to
introduce a big disclaimer because about
all of this biology
don’t trust me I’m an engineer actually
I studied electrical engineering at the
Technical University of Delft and I was
trained to build computer chips like the
ones in your smartphone now you might
ask how do you go from building computer
chips towards growing cardio the cardiac
cells that’s a good question and you
might also ask why well the why is
actually simple
I’m gonna show you this movie again
because I think this is absolutely
incredible
these cells are more ingenious than
anything we’ve ever ever engineered but
then the how how does it work what does
an engineer do in a developmental
biology lab well to be honest when I
started in that lab I didn’t really have
a clear idea as well but it turns out
that if we combine the biological
knowledge with the technological
knowledge that we can actually make
really complex tools like the one showed
here and I cannot go into all the
technical details of the system but what
we can do with it is measure the three
most fundamental parameters of the heart
simultaneously and this is the
electrical activity that you all know by
now and the contraction which is of
course the end goal of the cells and
finally the calcium and the calcium is
necessary for cells to contract now
these kind of systems we we can make
with this combination of technology and
biology and what we do is we have the
cells in a sort of a petri dish well
actually is a sort of plate with a lot
of petri dishes we grow ourselves there
then we add an optical chemical dye
inside and this optical chemical dye is
triggered by the leds on the other side
and then with the high-speed camera
that’s attached to the microscope we can
make a really nice recording with a high
temporal resolution so we can get a
really accurate measurement of what is
going on there and I’ll show you a movie
how that looks like in a bit but first
I’ll show you what the setup looks like
so it’s kind of dark you see a lot of
wires but if you don’t believe it really
takes an engineer to build this I made a
kind of an enlargement of a certain area
and you clearly see duct tape and dyrus
I can tell you it’s state of the art
engineering but what’s really cool is if
we is when we look through the
microscope and what I’m going to show
you is a movie of the cells that are
labels that are loaded with this calcium
sensor and every time the cells beeped
you see that the calcium sensor
increases in activity so these are again
human heart cells in a dish and on the
right side you see a graph and this
tracks the intensity of the cells this
tracks how many calcium is in it cells
and with this kind of tools we can
actually test what a drug does so there
are many drugs that have a negative
effect on the calcium in the cell if we
would add this this to it as well to
this piece of cells we will see that the
activity drops and this is exactly the
tool that we can use to test new drugs
however we still need to check whether
it works with the old drugs
that’s our validation set and this is
exactly what we’ve done we’ve worked
together with a pharmaceutical company
and they gave us ten drugs we didn’t
know which one was which and we had to
test them one by one using your system
now after a while we came back and seven
out of ten we had correct if it was
exactly what they and we predicted
exactly what they found in humans two
out of ten were completely wrong
and one well I think we were right they
think we’re wrong but we’ll settle in
the middle so it’s 75% correct I think
this is already really good but we want
to get to this hundred percent we use
human cells why isn’t it hundred percent
yet there are two reasons mainly one is
because we’re only looking at the heart
and it’s not an complex interplay of the
organs as we find in the human body and
the second one is that the cells are
still bit immature like you would find
in a newborn baby for example and we can
see this if we look at the electrical
activity again so the cells are in the
middle that we make and you can see this
electrical activity resembles the adult
electrical activity way more but it’s
not as good yet yet as the adult
compared to the mouse but it’s not as
good as the adult just yet the timing
and the shape is still a little bit off
and one of the reasons why it’s maybe a
little bit off is because the cells
don’t feel at home they’re in this petri
dish it’s
ridges they don’t like it in the heart
they are in his soft environment exactly
a nicely aligned in one direction and
they work together so what we try to do
and again engineering seems to be to
assumes to be the way to offer a
solution we made a really flexible soft
substrate and made really tiny grooves
of 20 micrometers inside and then we
grew the cells on top of them and this
is what we see the cells are now aligned
in one direction and they work together
to pull this piece of rubber up and down
and we were did this together with
engineers from the Technical University
in Delft and they took it to a step
further and they built this hard on chip
design device you can see a
cross-section of the design in blue you
see the cells and here you see again in
brown the the grooves in the flexible
substrate in the soft substrate now
there are also electrodes built into
this substrate so you can actually
measure the electrical activity of the
cells while they are contracting and to
make it even feel more at home
for the cells we also make this air
chamber which we can inflate and then
the cells are stretched and strained
just like they would experience when
they’re in the heart now this is what
this is the device looks like in real
life and you can see it’s really small
and making it really small is important
because we have we only need to use a
really small amount of cells which is of
course makes it makes it a lot cheaper
now by making it cheaper and more
accurate this is the way it’s going to
change the development cost for drugs
completely now we make this hard on chip
device but other people are making lung
on chip and skin on chip and actually
this whole field is called organ on chip
and in the Netherlands there’s just an
initiative that started where a lot of
scientists all over the Netherlands work
together to build mainly three different
organs which are the brain the gut and
and the heart and the idea is to to make
these exactly as the heart on chip with
cells from patients and
integrates the measurement methods etc
etc but not only make those three
devices separately but then couple them
together using a blood flow in between
and when we can change the microbiome
for example in the gut and see how that
affects the brain so we try to make a
complete avatar of a human on a chip we
try to make a complete avatar of you on
a chip if we use your cells now when I
talk about this you understand that we
need a lot of multidisciplinary research
to get this going and it’s good to get
this research further and what people
usually show when they talk about such
multidisciplinary research is a
schematic like this so we have this stem
cell biology field and we have this chip
technology field and where they meet
roughly in the middle there’s this organ
on chip field for example but I think
that’s wrong I think that’s the wrong
way to show it I think it’s different I
think if we think about this it should
be that this buy of the stem cell
biology field and the chip technology
field are separated and if people go out
of their own fields and meet each other
halfway we find an even bigger field
than the previous fields which is called
in this case organ and chip and this
happens every time so for example we are
during my research and organ on chip we
developed this software to quantify the
contraction of the heart muscle cells in
a dish and we showed it to medical
doctors and they were they were so
enthusiastic that were actually trying
it out in patients now so basically
we’re combining this organ on chip field
with the clinical field and again
there’s a huge increase in horizon and
this can happen again and again and
again think about it if we would combine
these technologies technologies with
complex data analysis or maybe if we
have a brain on chip maybe we can couple
it to human psychology and every time
our horizon will get bigger and bigger
and bigger and that’s why I believe if
we step out of our own fields
and cross that border swords eat each
other
that the possibilities are infinite
thank you [Applause]
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