well hello it’s great to be here I’m
going to tell you a story today that
intersects my life in brain surgery
neural stem cells and brain cancer and I
call it beyond brain surgery and I think
beyond brain surgery is science and
biology and that’s the future in my
daily work I get to see the human the
live human brain almost every day and
every day I’m absolutely marveled at how
this tan-colored three-pound organ
dictates and is embedded within our
feelings our emotions our skills our
knowledge how is it that biological
pulsating tissue can be the essence of
who we are and certainly I love this
quote from this physicist this
theoretical physicist from the US who
says who says the human brain is a
hundred billion neurons each neuron
connected to 10,000 other neurons and
and sitting on your shoulders is the
most complicated object in the known
universe just the complexity of the
human brain is absolutely astounding and
200 years ago we had a simple view of
what was going on the brain based on
examination of patience and
understanding of cos that affected them
and affected their functions and then
studying their brains after to see which
which regions were involved and so we
had this map for for movement of
different parts of the body and
different areas of feeling but now with
functional MRI with diffusion tensor
imaging we have an exquisite map of we
can obtain an exquisite map for every
person’s brain and it’s not that a text
book can’t tell the story of each
person’s brain we need to actually write
a text book for each individual person’s
brain and here you can see all the
different bundles of nerves that are can
interconnecting throughout a human brain
and as well Jeffrey Lichtman from
Harvard University has devised a method
in animals where he can label individual
neurons with different colors to study
the the cell the cell connectivity of
the of the brain and certainly these
approaches will come to humans in the
future but this is changing the way we
think about how these different circuits
define the essence of who we are and how
we function now as a neurosurgeon we’re
not we’re not quite at the cellular
level but certainly these advances in
technology are enabling us to do brain
surgery safer than we’ve ever been able
to do before and we can take this
information not just the anatomy not
just the shape of the brain but we can
take these maps of the different
functions for these four for example we
can take language and we can pinpoint
where language is in the brain so we
know if we have a lesion to remove in
the brain we can go around the language
area to remove the lesion and keep the
person’s language functions intact and
we can integrate this with computer
systems so when we’re doing surgery we
can point to areas in the head or in the
brain that tell us exactly where we are
with respect to the imaging and the
different functional pathways that we
want to protect and preserve and so
here’s here’s us we were pointing at the
brain in that patient and this tells us
relative to the scan where we are and
here just at the bottom left is a tumor
deep in this person’s brain that we’re
seeking to remove and so this is
incredible technology it’s advancing all
the time it’s allowing us to to devise
safe and better access to make brain
surgery a safer and safer and and as
well we have microscopes that allow us
to operate at at a millimeter by
millimeter level so I could spend four
hours in an area the size of the end of
my thumb to remove a tumor for example
and and carefully tease it away from
from nerves that might be responsible
for
a person swallowing or their ability to
speak for example so all of these tools
we have now at our disposal some brain
surgery has never been safer and so it
allows us to confront a very difficult
problem like this with some confidence
so here this this was a six year old
girl who had headaches she gets a scan
and she had this as you can see in the
middle that bright areas is a brain
tumor within within the very deepest
reaches of her brain and so we had a
real challenge how do we get to that
this needs to be removed she’s suffering
symptoms and so with those tools with
those maps we were able to sneak in in
between the two halves of the brain and
minimally disrupt the brain so as to
remove that person that person’s tumor
and they woke up beautifully after the
operation and everyone was relieved and
we were all feeling very good about what
we were able to do with our hands with
this great technology but the problem
with brain tumors is this is that they
come back and so unfortunately this
person’s tumor came back several years
later and it came back in a way that
surgery no longer had a role and so
first as a as a clinician and with this
knowledge cancer is a leading cause of
non accidental death and Canadian and
American children and brain tumors
represent many of these because other
types of childhood cancers are being
cured at a much higher rate for example
childhood leukemia and so for myself
being a brain surgeon and seeing wanting
to always push myself to do better and
to go beyond what I’d been taught I I
wanted to do much more than that I
didn’t want surgery to be the last step
I wanted to understand more and for this
we have to turn to biology what can be
done what can be done in science and
scientific research and this is really
what our main problem is for a lot of
cancers that affect many different
systems in the human body or
problem isn’t necessarily with with the
for the first the first forays into
treatment still surgery is a very
important part of treatment of cancer in
many different systems so it seems like
such a crude act to physically remove
but still today it’s still one of the
most important things that needs to be
done in order to treat a person’s cancer
but the problem is with recurrence so
recurrence after first treatment is a
main obstacle to cure for many cancers
including and especially brain cancer so
one of the cancers that were very
interested in which is quite common in
young young people is a tumor called
medulloblastoma and so I turn to
thinking about well first what what do
these tumors look like under a
microscope and so this is a typical
picture of a medulla blastoma where here
purple is staining the nuclei and pink
stains the cytoplasm of the cells and so
here there are many cells packed
together and essentially all of this
looks quite similar all the cells
morphologically look similar so I asked
a question is that really true are those
cells really truly the same and so we
started to ask that question by staining
tumors for different markers and we had
a clue that cancer of the brain might be
like an aberrant developmental process
based on stem cells and I’ll come back
to that more detail but so what we
wanted to do and this this this was from
a model of the same cancer that that can
be modeled in an animal and we stained
cells within that tumor with different
markers and so these these are markers
sox2 dcx and new end they represent
markers of stem cells progenitor cells
and mature cells of the normal brain and
so we find these normal markers also in
the tumor and this suggests that maybe
there’s a relationship between those
cells maybe this type of cancer
represents an abnormal stem cell system
and key point here is that the stem
cells which expresses gene
sox2 are relatively few but we think
those are the key cells so we faced with
that initial information we want to ask
this question our relationships between
stem cells and they’re more mature
daughter cell progeny maintained in a
cancer context and I’m going to show you
tell you show you a little bit of some
experiments that suggest that the answer
to that is yes there’s a lot of
excitement now over the last 20 years
that our brain is more dynamic than we
ever thought before because there are
several regions in the brain where there
are new neurons made in the brain that
that may play a role in for example in
memory formation in a part of the brain
called the hippocampus which is on the
inner part of the temporal lobe and
perhaps making new neurons is essential
to being able to generate new memories
but so the stem cells reside within they
generate other cells that amplify the
number of cells because they divide
frequently and ultimately they undergo a
process called differentiation or
maturation into cells that are neurons
or glia which are astrocytes are oolagah
dentro sites supporting cells for the
neurons and so in the normal context
during development that process works as
a baby’s brain grows during development
and there’s there’s more robust activity
of that early on in life in humans and
there’s that diminishes over time but in
the normal context to make that
beautiful brain that you saw those
pictures of that these processes are
extremely tightly regulated and are
beautifully orchestrated and I like this
image from one of my favorite records
that that that illustrates the this
process but in cancer we think all those
there’s a resemblance to that those kind
of relationships it’s now gone haywire
but there are some clues within that
tell us what we can do so another key
point is cancers often represent
distortions of our normal selves and to
take that one step further in the brain
is brain cancers represent a bear
and developmental processes and brain
cancers we think grow because they
contain genetically abnormal stem cells
that are our if you will on a misguided
mission to grow abnormal brain tissue
and so we need to understand that
process and so I’m just going to show
you one example of one experiment that
supports this idea and it’s it’s a
classical experiment that that
scientists who are interested in
development of tissues does it’s
something called a lineage trace and
it’s a definitive measurement of the
potency of a cell that’s marked in a
tissue and it tells us whether how well
that tissue can replenish and how how
that tissue matures and we wanted to ask
this question
those five percents those few little
green cells I showed you in that picture
that expressed this gene key gene called
sox2 could those cells be at the roots
of growth of this type of childhood
tumor and so a graduate student in my
lab robert van ER did the experiment it
was a very difficult experiment but what
he was able to do is he could we used a
genetic trick that was embedded into
animals that would that would grow up
medulloblastoma naturally and this model
is very close to the to the sharing the
same genetic changes in the same the
tumors look the same as the human tumors
they express the same abnormal genetic
programs as a human tumor so we thought
it was it was a terrific model and here
was something that you actually can’t do
in a human being but you can do in a
very good animal model so what Robert
was able to do is he could mark the Sox
to positive cells and show initially
that these were few cells in the tumor
and then what we did is we followed that
tumor over time to trace the progeny of
these mark cells and essentially what
happens here is that cell becomes
acquires a color core this red color
when that cell divided and generated two
daughter cells both the daughter cells
became red and then as they divided both
their daughter cells become red and over
time we wanted to watch to see if the
tumor turn
red and essentially and here’s the real
experiment it shows that the tumor grows
based on the division and multiplication
of a rare population of cells that
reside within strongly supporting that
this this type of tumor is driven in a
based on an aberrant stem cell system so
on the right you can see over several
weeks the tumor essentially turns red
and it came from few cells so these
cells we think are at the root of the
growth of this kind of cancer and the
key thing here is we then started to
test conventional treatments in in in
this model to see how do the
conventional treatments target these
different cell types in these in these
tumors and essentially what we found
here is that the usual treatments were
were fantastic at killing a lot of the
cells in the tumor we found good drugs
already that also work in patients that
are very good at at shrinking these
tumors and and improving the symptoms
but but what you may not be able to see
so well here but on the right is after
the treatment we see more red cells in
this tumor and what that means is that
the we spared a population of cells
we’re leaving something behind we’re
leaving a reservoir of cells behind that
may show the capacity to regrow the
tumor and and so in applying the stem
cell biology approach this developmental
framework if you will to thinking about
how cancer grows we can start to divide
up different cell types in the tumor in
two distinct compartments I’m not going
to go over all of this but essentially
there are a few cells that are that have
a stem cell property that actually
another key point about those cells is
that they’re very slowly dividing they
and our general treatments for cancer
are very good at targeting cells that
are rapidly dividing we figure that
process out but we haven’t figured out
so well how to deal with cells that are
lurking within the cancer that maybe
have a very slow dividing
potential seems like the drugs that we
have don’t target these slowly cycling
cells those cells in turn generates
progeny that divide fast which are
cancer progenitors which respond to
chemotherapy which we can wipe out and
eventually those cells undergo a
maturation process not like the normal
brain but still resembling the normal
brain but these cells that mature
actually are short live and are
eliminated and although they form a
component of the mass of the tumor which
can cause symptoms they actually
disappear over time they’re programmed
to disappear and it may be analogous to
what also happens in the developing
brain we during development we generate
way way more neurons than we need and as
those neurons start to make connections
a lot of the extra neurons are pruned so
we there may be this process is also
being recapitulated in this cancer
context but what this tells us also is
that we need different types of
treatments for these different types of
cells and applying the stem cell
thinking means we don’t we not we not
only have to target the fast awaiting
cells we need something that targets the
slow dividing cells or maybe what we
should do is just force all of these
cells to mature into these
differentiated cell types and then those
cells what cells will have a limited
lifespan and will disappear so I think
one of the key points I want to get
across today and I think it applies
generally to cancer is not every cancer
is functionally created equal even if
they may have the same genetic changes
they’re not behaving the same way and we
need to figure that out so cancer is
much more than genetic mutations genetic
mutations are essential to get cancer
growing are essential to be cancer but
but it’s how those genetic changes are
being used by the cells that also
dictates the way that cancer behaves so
we think that cancer reflects how
genetic changes shape the behavior of
normal tissue growth and regenerative
processes and in our in our group we’ve
identified a cellular target in
medulloblastoma
and also in glioblastoma of adults and
we’re starting to characterize more of
the programs that dictate the behavior
of those cells and we think that we have
the cell in hand that is responsible for
the root growth of these tumors but also
responsible for the recurrence having
these cells at hand
gives us the chance to discover new
therapies that may more that may better
affect long lasting cures so I think
there is hope for a better future for
for children and adults with brain
cancer based on applying this kind of
framework to understanding brain cancer
and it and really as someone who started
off as a clinician as a surgeon I love
what I do in looking after a patient’s
and being able to use my hands and to be
able to have a dramatic impact on
someone’s life
with an operation but I recognize that
still there’s limitations in what we can
do with our hands and I think we’re not
we’re not yet to be replaced by robots
because still there’s aspects of the
human motor and sensory systems that
still can’t be replaced by robots so we
need surgeons but we need much more than
surgery we need to understand biology
and I think the key for for young people
is science Canada and the world needs
more people engaged in scientific
research to ask creative original
questions and to think outside the box
we think in a way we thought outside of
the box and look and looking at brain
cancer this way and we’re very hopeful
what that might mean for the future
thank you very much for your attention
[Applause]
going to tell you a story today that
intersects my life in brain surgery
neural stem cells and brain cancer and I
call it beyond brain surgery and I think
beyond brain surgery is science and
biology and that’s the future in my
daily work I get to see the human the
live human brain almost every day and
every day I’m absolutely marveled at how
this tan-colored three-pound organ
dictates and is embedded within our
feelings our emotions our skills our
knowledge how is it that biological
pulsating tissue can be the essence of
who we are and certainly I love this
quote from this physicist this
theoretical physicist from the US who
says who says the human brain is a
hundred billion neurons each neuron
connected to 10,000 other neurons and
and sitting on your shoulders is the
most complicated object in the known
universe just the complexity of the
human brain is absolutely astounding and
200 years ago we had a simple view of
what was going on the brain based on
examination of patience and
understanding of cos that affected them
and affected their functions and then
studying their brains after to see which
which regions were involved and so we
had this map for for movement of
different parts of the body and
different areas of feeling but now with
functional MRI with diffusion tensor
imaging we have an exquisite map of we
can obtain an exquisite map for every
person’s brain and it’s not that a text
book can’t tell the story of each
person’s brain we need to actually write
a text book for each individual person’s
brain and here you can see all the
different bundles of nerves that are can
interconnecting throughout a human brain
and as well Jeffrey Lichtman from
Harvard University has devised a method
in animals where he can label individual
neurons with different colors to study
the the cell the cell connectivity of
the of the brain and certainly these
approaches will come to humans in the
future but this is changing the way we
think about how these different circuits
define the essence of who we are and how
we function now as a neurosurgeon we’re
not we’re not quite at the cellular
level but certainly these advances in
technology are enabling us to do brain
surgery safer than we’ve ever been able
to do before and we can take this
information not just the anatomy not
just the shape of the brain but we can
take these maps of the different
functions for these four for example we
can take language and we can pinpoint
where language is in the brain so we
know if we have a lesion to remove in
the brain we can go around the language
area to remove the lesion and keep the
person’s language functions intact and
we can integrate this with computer
systems so when we’re doing surgery we
can point to areas in the head or in the
brain that tell us exactly where we are
with respect to the imaging and the
different functional pathways that we
want to protect and preserve and so
here’s here’s us we were pointing at the
brain in that patient and this tells us
relative to the scan where we are and
here just at the bottom left is a tumor
deep in this person’s brain that we’re
seeking to remove and so this is
incredible technology it’s advancing all
the time it’s allowing us to to devise
safe and better access to make brain
surgery a safer and safer and and as
well we have microscopes that allow us
to operate at at a millimeter by
millimeter level so I could spend four
hours in an area the size of the end of
my thumb to remove a tumor for example
and and carefully tease it away from
from nerves that might be responsible
for
a person swallowing or their ability to
speak for example so all of these tools
we have now at our disposal some brain
surgery has never been safer and so it
allows us to confront a very difficult
problem like this with some confidence
so here this this was a six year old
girl who had headaches she gets a scan
and she had this as you can see in the
middle that bright areas is a brain
tumor within within the very deepest
reaches of her brain and so we had a
real challenge how do we get to that
this needs to be removed she’s suffering
symptoms and so with those tools with
those maps we were able to sneak in in
between the two halves of the brain and
minimally disrupt the brain so as to
remove that person that person’s tumor
and they woke up beautifully after the
operation and everyone was relieved and
we were all feeling very good about what
we were able to do with our hands with
this great technology but the problem
with brain tumors is this is that they
come back and so unfortunately this
person’s tumor came back several years
later and it came back in a way that
surgery no longer had a role and so
first as a as a clinician and with this
knowledge cancer is a leading cause of
non accidental death and Canadian and
American children and brain tumors
represent many of these because other
types of childhood cancers are being
cured at a much higher rate for example
childhood leukemia and so for myself
being a brain surgeon and seeing wanting
to always push myself to do better and
to go beyond what I’d been taught I I
wanted to do much more than that I
didn’t want surgery to be the last step
I wanted to understand more and for this
we have to turn to biology what can be
done what can be done in science and
scientific research and this is really
what our main problem is for a lot of
cancers that affect many different
systems in the human body or
problem isn’t necessarily with with the
for the first the first forays into
treatment still surgery is a very
important part of treatment of cancer in
many different systems so it seems like
such a crude act to physically remove
but still today it’s still one of the
most important things that needs to be
done in order to treat a person’s cancer
but the problem is with recurrence so
recurrence after first treatment is a
main obstacle to cure for many cancers
including and especially brain cancer so
one of the cancers that were very
interested in which is quite common in
young young people is a tumor called
medulloblastoma and so I turn to
thinking about well first what what do
these tumors look like under a
microscope and so this is a typical
picture of a medulla blastoma where here
purple is staining the nuclei and pink
stains the cytoplasm of the cells and so
here there are many cells packed
together and essentially all of this
looks quite similar all the cells
morphologically look similar so I asked
a question is that really true are those
cells really truly the same and so we
started to ask that question by staining
tumors for different markers and we had
a clue that cancer of the brain might be
like an aberrant developmental process
based on stem cells and I’ll come back
to that more detail but so what we
wanted to do and this this this was from
a model of the same cancer that that can
be modeled in an animal and we stained
cells within that tumor with different
markers and so these these are markers
sox2 dcx and new end they represent
markers of stem cells progenitor cells
and mature cells of the normal brain and
so we find these normal markers also in
the tumor and this suggests that maybe
there’s a relationship between those
cells maybe this type of cancer
represents an abnormal stem cell system
and key point here is that the stem
cells which expresses gene
sox2 are relatively few but we think
those are the key cells so we faced with
that initial information we want to ask
this question our relationships between
stem cells and they’re more mature
daughter cell progeny maintained in a
cancer context and I’m going to show you
tell you show you a little bit of some
experiments that suggest that the answer
to that is yes there’s a lot of
excitement now over the last 20 years
that our brain is more dynamic than we
ever thought before because there are
several regions in the brain where there
are new neurons made in the brain that
that may play a role in for example in
memory formation in a part of the brain
called the hippocampus which is on the
inner part of the temporal lobe and
perhaps making new neurons is essential
to being able to generate new memories
but so the stem cells reside within they
generate other cells that amplify the
number of cells because they divide
frequently and ultimately they undergo a
process called differentiation or
maturation into cells that are neurons
or glia which are astrocytes are oolagah
dentro sites supporting cells for the
neurons and so in the normal context
during development that process works as
a baby’s brain grows during development
and there’s there’s more robust activity
of that early on in life in humans and
there’s that diminishes over time but in
the normal context to make that
beautiful brain that you saw those
pictures of that these processes are
extremely tightly regulated and are
beautifully orchestrated and I like this
image from one of my favorite records
that that that illustrates the this
process but in cancer we think all those
there’s a resemblance to that those kind
of relationships it’s now gone haywire
but there are some clues within that
tell us what we can do so another key
point is cancers often represent
distortions of our normal selves and to
take that one step further in the brain
is brain cancers represent a bear
and developmental processes and brain
cancers we think grow because they
contain genetically abnormal stem cells
that are our if you will on a misguided
mission to grow abnormal brain tissue
and so we need to understand that
process and so I’m just going to show
you one example of one experiment that
supports this idea and it’s it’s a
classical experiment that that
scientists who are interested in
development of tissues does it’s
something called a lineage trace and
it’s a definitive measurement of the
potency of a cell that’s marked in a
tissue and it tells us whether how well
that tissue can replenish and how how
that tissue matures and we wanted to ask
this question
those five percents those few little
green cells I showed you in that picture
that expressed this gene key gene called
sox2 could those cells be at the roots
of growth of this type of childhood
tumor and so a graduate student in my
lab robert van ER did the experiment it
was a very difficult experiment but what
he was able to do is he could we used a
genetic trick that was embedded into
animals that would that would grow up
medulloblastoma naturally and this model
is very close to the to the sharing the
same genetic changes in the same the
tumors look the same as the human tumors
they express the same abnormal genetic
programs as a human tumor so we thought
it was it was a terrific model and here
was something that you actually can’t do
in a human being but you can do in a
very good animal model so what Robert
was able to do is he could mark the Sox
to positive cells and show initially
that these were few cells in the tumor
and then what we did is we followed that
tumor over time to trace the progeny of
these mark cells and essentially what
happens here is that cell becomes
acquires a color core this red color
when that cell divided and generated two
daughter cells both the daughter cells
became red and then as they divided both
their daughter cells become red and over
time we wanted to watch to see if the
tumor turn
red and essentially and here’s the real
experiment it shows that the tumor grows
based on the division and multiplication
of a rare population of cells that
reside within strongly supporting that
this this type of tumor is driven in a
based on an aberrant stem cell system so
on the right you can see over several
weeks the tumor essentially turns red
and it came from few cells so these
cells we think are at the root of the
growth of this kind of cancer and the
key thing here is we then started to
test conventional treatments in in in
this model to see how do the
conventional treatments target these
different cell types in these in these
tumors and essentially what we found
here is that the usual treatments were
were fantastic at killing a lot of the
cells in the tumor we found good drugs
already that also work in patients that
are very good at at shrinking these
tumors and and improving the symptoms
but but what you may not be able to see
so well here but on the right is after
the treatment we see more red cells in
this tumor and what that means is that
the we spared a population of cells
we’re leaving something behind we’re
leaving a reservoir of cells behind that
may show the capacity to regrow the
tumor and and so in applying the stem
cell biology approach this developmental
framework if you will to thinking about
how cancer grows we can start to divide
up different cell types in the tumor in
two distinct compartments I’m not going
to go over all of this but essentially
there are a few cells that are that have
a stem cell property that actually
another key point about those cells is
that they’re very slowly dividing they
and our general treatments for cancer
are very good at targeting cells that
are rapidly dividing we figure that
process out but we haven’t figured out
so well how to deal with cells that are
lurking within the cancer that maybe
have a very slow dividing
potential seems like the drugs that we
have don’t target these slowly cycling
cells those cells in turn generates
progeny that divide fast which are
cancer progenitors which respond to
chemotherapy which we can wipe out and
eventually those cells undergo a
maturation process not like the normal
brain but still resembling the normal
brain but these cells that mature
actually are short live and are
eliminated and although they form a
component of the mass of the tumor which
can cause symptoms they actually
disappear over time they’re programmed
to disappear and it may be analogous to
what also happens in the developing
brain we during development we generate
way way more neurons than we need and as
those neurons start to make connections
a lot of the extra neurons are pruned so
we there may be this process is also
being recapitulated in this cancer
context but what this tells us also is
that we need different types of
treatments for these different types of
cells and applying the stem cell
thinking means we don’t we not we not
only have to target the fast awaiting
cells we need something that targets the
slow dividing cells or maybe what we
should do is just force all of these
cells to mature into these
differentiated cell types and then those
cells what cells will have a limited
lifespan and will disappear so I think
one of the key points I want to get
across today and I think it applies
generally to cancer is not every cancer
is functionally created equal even if
they may have the same genetic changes
they’re not behaving the same way and we
need to figure that out so cancer is
much more than genetic mutations genetic
mutations are essential to get cancer
growing are essential to be cancer but
but it’s how those genetic changes are
being used by the cells that also
dictates the way that cancer behaves so
we think that cancer reflects how
genetic changes shape the behavior of
normal tissue growth and regenerative
processes and in our in our group we’ve
identified a cellular target in
medulloblastoma
and also in glioblastoma of adults and
we’re starting to characterize more of
the programs that dictate the behavior
of those cells and we think that we have
the cell in hand that is responsible for
the root growth of these tumors but also
responsible for the recurrence having
these cells at hand
gives us the chance to discover new
therapies that may more that may better
affect long lasting cures so I think
there is hope for a better future for
for children and adults with brain
cancer based on applying this kind of
framework to understanding brain cancer
and it and really as someone who started
off as a clinician as a surgeon I love
what I do in looking after a patient’s
and being able to use my hands and to be
able to have a dramatic impact on
someone’s life
with an operation but I recognize that
still there’s limitations in what we can
do with our hands and I think we’re not
we’re not yet to be replaced by robots
because still there’s aspects of the
human motor and sensory systems that
still can’t be replaced by robots so we
need surgeons but we need much more than
surgery we need to understand biology
and I think the key for for young people
is science Canada and the world needs
more people engaged in scientific
research to ask creative original
questions and to think outside the box
we think in a way we thought outside of
the box and look and looking at brain
cancer this way and we’re very hopeful
what that might mean for the future
thank you very much for your attention
[Applause]
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