[MUSIC PLAYING]
It's my great pleasure to
introduce the next speaker, Dr.
Nadia Rosenthal.
She's the Director
of the Institute
for Regenerative Medicine
in Melbourne, Australia.
And Nadia had an interesting
professional journey.
Because she worked
all over the world,
including in Italy for 10
years, UK, France, and now
she's Australia.
And I just heard that she will
come back to the States soon.
But I was always impressed
by the faithfulness
that Nadia had to her
science and her mission,
which was really to understand
the biology of muscle and heart
stem cells to understand
the signals and the growth
factor that are fundamental for
the expansion of these cells,
with the ultimate goal to
bring therapy to patients
with incurable diseases.
So it's really an honor
for me to introduce Nadia.
And I thank you for being
here from Australia.
Thank you.
Good morning, it's
wonderful to be here.
The weather's almost
as nice as Melbourne.
And I'd like to spend the
next few minutes giving you
a bit of a taste of what
happens behind the scenes.
We've heard about the
extraordinary advances
of clinical practice and trials
in the gene and stem cell space
from Martin.
And what I do is
I'm just a nerd.
So I work behind the
scenes at the bench.
And I want to tell you about
the way we're going, thinking
about the way in which
the problems we've
heard about from several of the
speakers in childhood diseases
where regeneration is
absolutely critical
to the healthy functioning of
the adult play out in the lab.
So I've been obsessed all
my life with this issue.
Why is it that these other
organisms-- such as planaria,
little flat worms,
or salamanders,
or any of these wonderful
marine creatures like sea
urchins that you
find in the pools--
why can they regenerate?
And we can't?
It's not like we're missing huge
chunks of genomic information.
If anything, we have more.
And, yet, we seem to have
forfeited this capacity
to regenerate for
some unknown reason.
So what genetic
programs have we lost?
We really don't
know that answer.
But I'm going to explore
a few of the ideas
that we are coming up with
in the next few minutes.
One of the things
that's very clear
is that we aren't that
bad at regenerating.
So we couldn't have
lost that much.
Because as fetuses, we're known
to be very good regenerators.
Mammals can regenerate
large chunks of their body
as fetuses.
And, indeed, even
neonates-- as clinicians
know-- have an extraordinary
capacity for repair.
So we think that the basic
tools and tricks of the body
are still there.
But they somehow get
muddled up as we get older.
And it doesn't take long.
Because as you know, even by
the time you're an adolescent
you're not as good
at regenerating.
So the advent of
regenerative medicine
is a new area that's
really just about a decade
old seeks to identify
the mechanisms whereby
we've lost that capacity
to replace and restore
our tissues.
And to ask very
simple questions,
like why we can't
grow back that limb?
Or why we can't restore
muscular dystrophic tissue that
has been lost due to a
basic genetic defect?
So I'm just going to
give you a bit of a tour
through some of the areas
that we are thinking about,
and the way we're approaching
this problem at the coalface.
So, of course, stem
cells are a great feature
of regenerative medicine.
In fact, most people don't
think regenerative medicine is
anything other than stem cells.
In fact, when I
decided I was going
to try to call this
institute in Australia
the Regenerative Medicine
Institute, one of the deans
said to me, but isn't
that just stem cells?
So I had to explain to
him that one is a tool.
And the other is a discipline.
So what we're going to
talk about here is a tool.
And they're very
important tools.
And as you know, a stem
cell is essentially
a cell that can regenerate
itself over and over again, as
well as become many
different kinds of cells.
And, of course, the
ultimate stem cell
is the pluripotent
egg, or fertilized egg,
which makes a human being
or a mouse every time.
However, there are,
obviously, ways
in which we can think about
using stem cells in a slightly
less dramatic way.
But it's just as
important clinically.
And that is to treat
a number of diseases.
And there is an enormous
amount of promise out there.
And, indeed, these are some
of the areas where people
have considered using stem
cells to replace tissues
in a regenerative
medicine scenario.
So I'm going to go over a little
bit about what stem cells today
are being used for.
And we all have heard
of embryonic stem cells.
They're the famous ones that
can make any tissue in the body.
There's a lot of controversy
because of their origin
in human embryos for humans.
But they do perform these
extraordinary feats of becoming
all these different issues.
And we can use them to
understand development.
And as a result, they are an
extraordinarily important tool
in developmental biology.
And, indeed, very recently--
although I never thought
I would say this.
I had a slide actually
in this talk that said,
it'll be decades before
we use embryonic stem
cells in the clinic.
So I had to take it out.
Because we're already doing it.
And this is a case in point.
Very recently several groups
in Japan and in the UK
have used embryonic stem cells
to apply to the degenerating
back of your eye which
creates a scar seen here
in this white area.
And by applying this to a very
localized part of your body--
namely an eye, which is
sort of immunoprivileged,
a little bit isolated for
the rest of your body,
so a really great
place to try this out.
There appears to be, at
least safety-wise, no problem
with putting embryonic
stem cells in there.
They become the right thing.
And so far they've been
quite impressive in terms
of the capacity
to restore vision.
So this is amazing.
I'm very excited that this
has happened so quickly.
Now, more frequently you
hear about adult stem cells.
And adult stem cells
are simply the cells
within your own body--
once you have been born
and you have all these
different tissues--
that are responsible for
renewal of the tissues
that you already have.
So, for instance, the
reason that we don't all
look like cauliflowers
by this point in our life
is because we're
continuously regenerating
things in the right way.
So our skin is
regenerating skin.
Our intestines are
regenerating intestines.
And our blood is making
new blood all the time.
And some of our body is
very good at regenerating--
our liver, thank God.
And other parts of our body are
not so good, such as our brain,
as we heard about
before, and our heart.
So it's not clear just
exactly how these difference
tissue-restricted cells work.
And there's been a lot
of confusion about just
how pluripotent they are.
So can you take a
cell out of a muscle
and make it into a blood
cell, or the opposite?
Can you take a brain cell and
make it into something else?
And depending on
who you talk to,
there's a variety of opinion--
the most extreme of which
is that there are
certain cells that
become cells for that particular
tissue and no other tissue.
And other people feel
there's more plasticity.
And we're still-- I
think the jury's out.
There is one case
in point, however,
where there is no
question of pluripotency.
And that is in the blood.
And we're sitting in the home
of Irv Weissman, who is really
the father of this whole field.
And we know that,
indeed, we've been
using stem cell therapy
ever since bone marrow
transplants were
discovered and started
to be used in some detail.
And we've been just
hearing about some
of the extraordinary
capacity for bone marrow
and cells of the immune system
and the hematopoietic system
to form a really
important clinical tool
for treating blood diseases.
And so in the case of a
hematopoietic stem cell,
it can become every
single cell type
of the blood in the
right condition.
And this is, of course, the
prime example of an adult stem
cell that is pluripotent.
So as a result, stem
cells in the adult
have become very exciting.
And there's rumor of cells
that are stem cells in capacity
to rebuild your body from
something as unlikely
as your adipose tissue.
There are other cases where
people have used fibroblasts.
There's a lot of hype.
And, indeed, if
you go to Mexico,
you can have it done on the
beach apparently, which really
always makes me wonder just
exactly what's going on
at these places.
And I think as we
all know, there's
a considerable amount of
concern about the safety of some
of these less
well-controlled institutes
where this is going on.
But it's an area that
I think is really
going to gain in importance.
So one of the things that
happens when adult stem
cells are created is that if
they are not from yourself,
they could create
an immune response.
And one of the ways
around this is--
and one of the ways around
using embryonic stem cells--
is the new induced
pluripotent stem cell.
And this is, just
by way of review,
a very well-established but
very rapidly-established
new technology-- for which
several people won the Nobel
Prize a couple of years ago--
in which a run of the mill
fibroblast out of
your body, literally
out of the side of your
cheek or anywhere else,
can be reprogrammed
to re-capitulate
the entire developmental process
of your own embryo genesis
such that you produce
a stem cell that
can become many other kinds
of cells in your body.
And, of course, because
it's your own cell
the genes are your own genes.
And the proteins are
your own proteins.
They'll be no immune response.
And they, in theory, could be
the perfect precision medicine
tool.
And, indeed, here
are two examples.
You see at the top there's an
example of four different genes
that are being introduced
into fibroblasts
and producing a cell
that is pluripotent,
and therefore can become
any kind of tissue.
And at the bottom,
more recent advances
allow you to very
transiently introduce
these factors which otherwise
might be quite dangerous.
Because, of course, they're
important for embryo genesis.
But they could also
be cancer causing.
So there's a lot of
technology around this.
It's a very exciting field.
And we're using it as
scientists to know much more
about the developmental
process that
takes us from the
fertilized egg to the baby.
Here's just a few
examples of the idea
behind the
pluripotent revolution
where you take a
patient's stem cell.
Turn it into the
cell they're missing.
And reintroduce
it into the body.
You can also use these cells
for pathological studies,
toxicology studies, and also,
of course, for drug discovery.
And, indeed, there have
been some real advances
in this field.
Just recently there was
a beautiful study looking
at stem cells that were
derived from the fibroblasts
of patients that had
dementia-- looking at the gene
mutations in those patients,
and correcting the gene mutation
in the patient using gene
editing technology in the cell.
And then looking to see
how those cells were
capable of differentiating
back into neurons.
And although there is a lot of
hurdles to still be overcome,
the concept is really there.
The proof of principle is there.
So what are the limitations
of stem cell therapy?
Well, one possible
limitation is how do you
get from a cell that is
pluripotent to a cell that's
differentiated?
And how far do you get?
And in other words,
if you get a neuron,
is it a neuron that will really
do what you want it to do?
Will it learn how
to play the piano?
And it's not clear
that we're really
in possession of the
tools that will allow
us to make those final
decisions about very, very
refined differentiation.
And specifically, when
you transplant a cell
into a body without
that information,
I always liken it to having
someone parachute out
of an helicopter into the
Gobi Desert with no cell phone
or any other instruments of
sustained viability like water.
And how would you expect
someone in a business suit
to survive there?
And in some ways, I think
of stem cells that way.
When you introduce
them into the body
they are completely
out of context.
And for the most part, they die.
So, really, the functional
integration of stem cells
back into the body
is something that
is an extraordinary
hurdle that really
isn't talked about enough.
So one reason why I
think this is a problem
is because we don't
really understand
this very, very fine balance
between the inflammatory
response that occurs in injury
and in degenerative disease,
and the cell replacement
that must eventually
supplant that information.
So what normally happens
is in a very healthy kid
an injury produces a rapid
response of the immune system
to produce the inflammation
necessary to guard
against infection and
to clean up the mess.
But then very quickly after
that, the inflammatory response
is quelled.
And cell replacement starts,
be that stem cell or other,
so that scarring is avoided
and repair is favored.
And that tipping of the
balance is something
that we don't know much about.
We know that it can be done
very easily in the fetus.
We know that balance
is definitely skewed
as we get older in
the wrong direction.
So in my Institute
in Australia we've
taken the attitude
that, again, because we
know that there are organisms
out there that can do this
effectively as adults
and don't scar,
perhaps we can learn from them.
And here are just a few of them.
There's zebrafish
there on the left,
and my favorite new organism
the axolotl in the middle,
and a little mouse on the right.
So the idea would be
learning from the variation
within the natural
animal kingdom
will allow us to apply this
basic principles in the clinic.
So here, as I said, is
my favorite new organism.
It's always a winner.
Because it looks
like something that
comes from Mars, or definitely
from Steven Spielberg.
But it is actually a
real live organism.
It's an aquatic salamander.
They live in Mexico.
I think there's the
second allusion to Mexico.
I must be heading for Mexico.
So these animals are scar free.
They will heal
just about anything
you cut off them
other than their head.
And they are extraordinarily
robust in their capacity
throughout life to do this.
So the question is,
why do they die?
And that's an
interesting question.
I'll get to that in a minute.
We think that maybe their
immune system is different.
Because they never scar.
And we know that
inflammation is a function
of the immune system.
And it seems like
it's quite different.
And it allows these animals to
reconfigure their entire limb,
or tail, or heart, or
jaw, recapitulating
the entire
developmental sequence
within a very short time, and
making something much bigger
than they made at the beginning.
Because, of course,
they started off
with eeny-weeny,
tiny, little arms
when they were eeny-weeny,
tiny, little salamanders.
Now they've got to grow
back a whole adult one.
And they do it in the
same amount of time.
So one asks, why would
these animals do this?
I mean, why would they be
able to grow these limbs back?
And the answer is, because they
eat each other up all the time
when they're stressed, or
hungry, or crowded, sort
of like academics.
And they continue to sort
of munch on each other.
So the way I got this
through the ethics committee
down in Australia.
They have a very strict
ethics committee.
And I said, I'm going to cut
off the limbs of salamanders.
And they said, I don't
think this sounds very good.
And I said, I'm doing
it with anesthesia,
unlike the real world.
So they are very, very good
at regenerating, I think,
because of just
evolutionary necessity.
And what is different?
Well, if you look at the
way immune cells arrive
at an injury during
the repair process,
there's a stately progression.
And this is a picture from the
way it looks in most mammals.
You have these neutrophils which
are pro-inflammatory cells,
and then macrophages, which
are sort of phagocytic
and eat up other cells
that are diseased or dead.
There are T cells,
which are part
of the adaptive immune system.
Everybody's on board.
But it usually takes
about five days for this
all to happen during an
effective regenerative response
in a mouse or a child.
The axolotls do it in 24 hours.
There's a giant cocktail party.
Everybody comes together.
And they arrive at the
scene within hours.
And we don't know
what that means.
But we suspect that
there's an acceleration
of the entire inflammatory
response that's
very important for the
effective regenerative process
to continue.
So we did a little experiment.
I'm not going to give you
too much more data at all.
But I'm just going to tell
you a couple of experiments.
Here we eliminated
one of the key parts
of the immune response,
which is macrophages.
And we did this by essentially
having them self-destruct.
It's not important.
To ask the simple question,
do macrophages there-- looking
at the purple
people eater there--
do they actually play an
important role in regeneration?
Or are they just coming
along for the ride
as an inflammatory cell?
We know that macrophages
do a number of things,
including protect
against infection.
But, interestingly,
during cancer
metastasis they also chaperone
cancer cells around the body
and get them to extravasate
out of the circulatory system
and move into new areas.
And it's that cooperation--
that very, very nefarious
cooperation, which actually
allows from metastasis
to continue.
So we wondered whether in
the regenerative context
this same kind of chaperone
approach was going on.
Because often cancer
and regeneration
are two sides of the same coin.
And so what we did was to cut
off the salamander's limb,
either with or without
macrophages in its system.
And I think this is a
self-explanatory slide.
Because you can see that the
new limb that is now grown out
from that cleavage site, which
is the dotted line where we cut
off the limb, it's just magic.
It grows out.
And becomes a fully functional
and completely re-capitulated
structure.
But without macrophages
even for a few days
right at the beginning of
the process of healing-- even
if they come back later,
which they do very quickly--
the poor little guy never heals.
Because there's this
massive scar there.
And, essentially, there's
never an outgrowth.
And the animal
remains completely
stumped for the
rest of its life,
unless you cut off a
little bit of that scar.
And you reactivate the system.
In which case, boom, the
thing starts up again.
So, clearly, you haven't changed
anything in the long run.
You've just blocked a
system which is ready to go,
and for some reason needed
macrophages to do it.
So here's my dream without,
obviously, total hype here.
But this is one of the
happiest Olympic stars
from Australia-- Paralympic
star from the 2012 Olympics
in London.
And wouldn't it be
nice if we could
find a way to change
her macrophage response
and grow back that limb?
Just a joke, anyway, macrophages
do a number of things.
And so the question is,
what are they doing?
And what does this have to do
with regenerative medicine?
Well, it turns out
that macrophages
are involved in angiogenesis
fibrosis, immune modulation,
cell survival, as well as their
cleanup mode that we think of.
And in each case they
make a particular factor
which I'm particularly
interested in called
insulin-like growth factor 1.
And so every single one of
these functions requires IGF 1.
So we wanted to know
whether there was something
magical about this
particular growth factor
that macrophages make.
And we know that it's important
for growth in the body
during embryo genesis in
early life and childhood.
But that later on, it's made
exclusively by the liver.
And it's essentially there
for endocrine functions.
And has some overlap
with the insulin.
So we know from work we've
been working on for a long time
when I started in Rome, making
mice that over-expressed
IGF 1 in their skeletal.
And they get very,
very muscular.
They're sort of
Schwarzenegger mice.
I was famous for 15 minutes
there when it hit the news.
But, more importantly,
when you injure these mice,
they regenerate
much more quickly.
And they do it in a way
that essentially resolves
the inflammation much
more quickly, just
like the salamander.
So by simply adding one
factor, one additional factor,
we've managed to change the
course of the traumatic injury
to muscle.
And here you see an experiment
we did a long time ago
showing that, indeed,
muscular dystrophy, which
is in this case modeled
in the MDX mouse,
could be countered by
the presence of IGF 1.
So it looked good.
And so we wondered where
it was coming from.
And fast forward 10 years,
Jo Tonkin in the lab
has done an extensive study
to show that during the injury
response macrophages
arrive at the scene.
And they absolutely flood
the area with IGF 1.
And if you use genetic tricks
to reduce the IGF 1 only
in the macrophages, you
essentially end up with muscle
that cannot regenerate.
So that means that almost all
of the IGF 1 that's normally
a spike during the
regenerative response
is absolutely critical.
And it's coming
from macrophages.
And without it, you
can't regenerate.
So the possibility
then remains--
and I'm not going to go into the
details of exactly what we're
doing.
But we're obviously involved in
therapies and trials involving
IGF 1.
The idea would be to
use the immune cells
as a kind of Trojan
horse to bring
these naturally-occurring
molecules in.
And, perhaps, increase the
capacity for regeneration
by allowing the immune
system to do the job.
And the idea would be
that a pluripotent stem
cell that you could, now you
know, get out of a patient
could be modulated to
produce therapeutic factors.
And we have other
data to suggest
that the adaptive immune
system, the T lymphocytes,
also make IGF 1 for
the same purpose.
OK so, finally,
just one more story,
the heart that can't heal.
We know that the heart
attacks in adults
are very, very
likely to be fatal,
or at least the
morbidity associated
with a heart attack
resulting in heart failure
is a serious problem
in our society.
The reason for this is that the
heart-- unlike the salamander,
or our skin, or
our blood-- simply
doesn't seem to be able to
regenerate at all once it's
formed.
However, what's interesting
is that very recently it's
been realized that neonatal
mice can regenerate their hearts
just as well as
a salamander can.
And that this is
something that gets
lost within the first
seven days after birth.
Now, remember, mice get born
at a much more premature stage
than a human.
So we would be looking
at late fetal life
in the human context.
But for a mouse that's
born at this stage,
they are literally
fully regenerative.
And, more interestingly
than that,
we've discovered very
recently that if you
look across different
mouse strains
they regenerate
completely differently.
And this was something that
Matt Gillman brought up earlier,
this idea of the context
of the individual.
So it turns out there's some
individual mice that regenerate
almost as well as the mice where
we make IGF 1 over expression.
And others that regenerate
much, much worse
than our normal mouse models.
And so we're now
beginning to use
that as a genetic tool to
map out the complex traits
associated with regeneration
in an unbiased way.
So if we look at
patients, we know
that certain patients
recover from heart attack
much more easily than others.
And the question
in my lab now is,
what is it about this
variability within patients
that we can model in an animal
model such as the mouse?
And, more importantly,
can we use
those regenerative
variations within species
to develop new tools
to treat the disease?
And, specifically, we've
used IGF 1 in this case
to over express in the heart.
And shown that, indeed, just
over expressing IGF 1 alone
is enough to
literally recapitulate
the more regenerative
capacity of a neonate.
Not surprisingly, the neonate's
making a lot more IGF 1.
I'm not saying this
is the only factor
important for regeneration.
But I'm saying that if you
use it as a sort of a hook
to pull out the
rest of the network,
we may be able to
understand the complexity
of the regenerative response.
So just in conclusion, I want
to make a couple of points.
One is that there's
not going to be
one therapy that's
going to do the job
for regenerative medicine.
It's going to require
stem cells, genes,
and probably scaffold as well.
So that gives that parachuter
something to come down in,
maybe a bubble of
other things that
would help survival-- a camel
someone once said to me.
Just give them a camel.
So maybe that's what
the scaffold will be.
And, indeed, when
we look at some
of the more recent ways in
which stem cells have been used
in heart repair-- there's
a very beautiful study
out of Minneapolis just
published a few weeks ago
where a patch of
essentially biomaterial
was infused with little spheres
containing slow release IGF 1.
And that patch was capable
of helping with the healing
of an infarcted heart.
But it was not
necessarily any better
than putting in
induced pluripotent
stem cells that had been turned
into various kinds of heart
cells.
But when you put them together,
you got a really good response.
Namely, if you had the IGF 1 in
that patch overlaying the stem
cells that you had
injected into the heart,
then you saw some really
much better recapitulation
of the regenerative tissue.
So that's just
one example of how
I think the whole
thing is going to work.
So in summary, this
is what I've told you.
Stem cell-based
therapies are promising.
We need to know a lot more.
Early resolution of inflammation
is a major determinant
and is very important.
And the future
advances will involve
thinking about how we treat
individuals rather than groups,
looking at the way in
which immune systems--
the individual variation
in people's immune systems
may play a great role in
allowing our stem cell-mediated
therapies and gene
therapies to work.
And then, finally, the
combinations of all of these
together is probably
going to be what
it needs to regenerate a body,
just like it does in real life.
So here are just some
of the people that
have done the work in the lab.
I don't have time to go into
all the wonderful post-docs
and students that have taken
this forward over the years.
And I'd like to also
thank my sponsors who have
made all this work possible.
Thanks for your attention.
[APPLAUSE]
