UCL Lunch Hour Lecture: Prometheus and I: building new body parts from stem cells Professor Martin Birchall (UCL Ear Institute) Prometheus created life from …
>> Thank you very much.
Couple of riders to this,
firstly, I'm a throat specialist
and I have laryngitis so
[laughter] I apologize
if I've not quite got the
volume that I normally do
and if it fades a little bit and
I'm taking some sips from that.
Also if you're kind of expecting
to hear detailed science
about stem cells,
you're not gonna get it
because I'm a surgeon and I rely
on the broad team of scientists
at UCL to tell me
at all scientific.
So but I will do my best to
answer questions at the end
and hopefully what I present
today will be an overview
of where I feel we might
be in terms of being able
to build organs using
stem cells.
I'm going to first of all
explain the background
to my own work, give
you some examples
of how we've applied stem
cells to build some organs
and put them into people and
then I will also then follow
by explaining what
problems we've encountered,
which I think will give
you an idea as well,
we need a lot more
work in future.
I'm disappointed we're not at
the point where we'll be turning
around and being able to
offer you new organs all
around this lecture theatre
at the end of the lecture
but in some years, who knows?
And then I'll at the end
just tell you a few areas
where we're going at the
moment worldwide in other parts
of the world, in terms
of developing organs
with stem cells so that's kind
of what we're going to do.
So you can put the
word surgeon in there.
Surgeons are very humble
fellows and they're very,
if any of you have ever been
business associates you'll know
how humility is the hallmark but
this is, from this book here,
which is a very good
read, actually.
Philip Ball, he used to write
for the BMJ and it's a book
about mans desire to try and
recreate man, keep life going,
be a bit God like
and recreate life.
And there's lot of it in there.
And he's not being
complimentary when he says
that these people become
Prometheus, as you will see.
Okay so I'm a head and neck
surgeon and I work a lot
with head and neck cancer
patients historically,
rebuilding people after they've
had cancer surgeries is a really
major challenge.
And many of the techniques
we use are very old.
They have been improved
upon by rehabilitation
but we're still very
limited in the number
of things we can do for people.
Surgery has actually taken a bit
of a backseat in recent years
to using chemotherapy
and radiotherapy
because of limitations of the
ability to regenerate things.
And the idea is that you use
chemotherapy and radiotherapy
to preserve organs so you do not
actually have to take them out
and the same is true for
bladders and uterus and lungs
and breasts, organ
preservation treatments.
The trouble is that a lot
of the organs left behind,
no longer function the way they
should so these things are a bit
of a blunder bus, a bit
unpredictable who they affect
so we're still left
with the idea
that if we could actually raise
the threshold of these surgeries
that we could provide people
with functional organs
and then may not have to
use such toxic treatment.
Furthermore there's
a huge shortage
of transplant organs worldwide.
Transplantations now mainstream
but it has a lot of issues,
availability of donors,
the ethical issues,
the religious issues,
the possibility
of transmitting infection
and of course the use
of immunosuppression.
When you put someone
on immunosuppression
after an organ transplant, you
reduce the length of their life
by perhaps up to 10 years.
That's a major handicap.
So rebuilding organs
would be a great thing.
This is somebody with a
completely closed over larynx
and somebody whose larynx is
fixed in the open position due
to trauma so there's
a wide variety
of reasons why I might want
to replace people's organs.
The convention operating factor
for treating larynx
cancer is laryngectomy
where you take the
whole thing out.
It's very effective.
But it's actually the same
operation that was invented
in Vienna in 1863 and it's
not changed in that time.
So we really should
be doing rather better
by applying science today.
Is the loss of laryngeal
function so bad?
Well if you don't want to
listen to what I'm saying,
it's probably a good thing
losing laryngeal function.
So it is about, well actually
if any of you want to go
out for a meal tonight,
you're going
to be using your larynx quite
a lot, not just for talking
but you actually
need your larynx
to protect your lungs
when you swallow.
That's the main function
of the larynx is
so that you don't
aspirate food and drug.
Oh, it's lunchtime.
You're eating now so you're
using your larynxes right now
so you don't get pneumonia
from eating and drinking.
You also need to fix
air in your lungs
in order to be able to strain.
You need to fix the vocal chords
together to be able to cough,
lifting heavy weights,
any of these things.
You also need to add going
through in order to sniff
and to taste and to taste
their food and smell it,
they need a functioning
larynx too.
At the end of this meal,
should they be close friends,
there may even be some kissing
going on and for kissing too,
you need air going
through your lips.
You can try that at home or you
can try that now if you want.
I'm very open-minded so
that's not a real problem.
[laughter] So it does
have a major effect.
And of course the voice,
the voice, and about 1800,
20% of people use their voice
as their main tool of work.
And despite the expansion
on the internet and so on,
something like 80% of people
working today would regard
to their voices, absolutely
critical to how they function
so maintaining your voice
is a critical issue.
How might you replace an
organ, larynx or anything else?
Well you can rebuild
things with bits of tissue
that are just lying around.
For example, if we take
out the jaw for cancer,
you can borrow the fibula,
the bone inside the leg here,
with skin over it and with
an artery vein attach it
and plum it into the neck.
You can break the fibula,
replate it into the shape
of a jaw and then
put it back in place.
So that's a very good example
how we can use other parts
of the body to rebuild
parts that are missing.
But you always will
have a donor site
and that has donor
complications from doing that
and you can have
fractures and so on,
plus the tissue never
looks the same.
It never really completely
functions the same.
It can scar up.
It isn't sensate.
It doesn't feel anything.
And getting autologous tissues
to move again is a really,
really major challenge.
So they're definite limitations
and it doesn't look
the same either.
So it's not perfect.
And for complex organs that
are doing things, like kidneys
and livers and so on, you're
really never going to achieve
that through moving other
bits of the body around.
Prosthetics were a great
idea, tried in the 70's
for various things, but actually
making plastic or metal stick
in the body is very difficult,
particularly if they're exposed
to the air or the
mucus membranes,
which are highly colonized.
Getting things to stick and
to function is very difficult.
So prosthesis have
never really done it.
Allografting, this is the
classical transplantation.
I've already been
through its value
but also there're really
significant drawbacks
about the way we apply
transplantation today.
And then there's regenerative
medicine, which is this new,
exciting field where we can
possibly regenerate tissues
and organs.
Actually it's not that new,
as you'll see in a minute.
Okay so this is the world's
first laryngeal transplant,
classical allograft.
And this is kind of what
I was working on for most
of my research career was how
we could do better transplants
with head and neck tissues.
And this is the first
one done in Ohio in 1998.
The patient is still okay
today and he's worked
as a Professional
Motivational Speaker
but he's always had a
tracheotomy cause he couldn't
get the nerves to work, or
they couldn't, and he's still
on immunosuppression and
his voice is starting
to fade a bit now but
he's doing pretty well.
And then in, okay, okay so a
couple years ago I was phoned
by my friend, Peter Glasgy,
[phonetic] University
California Davis,
to say he had an
exceptional patient
who not only had a totally
destroyed larynx and airway
but was also already
on immunosuppression
because she'd had a
kidney transplant.
So in a way she was
an ideal candidate
to do the world's second
laryngeal transplant
and we did most of the work in
between times on getting nerves
to work, on understanding
the immunity a lot better
so we thought we were in
a better place to do this.
So last year a team from Europe
and from America got together
and we transplanted an organ
into a 50 year old lady
from California and this is what
it looks like, at least looked
like at the beginning
of the year.
[inaudible background
talking] It moves.
It's sensate.
It's in the right place.
It doesn't move perfectly
and she's taken a long time
to start swallowing again
but clearly it looks
and moves just like a larynx.
So that was a guarded success.
She also got a tracheotomy
tube blocked off now
so that's quite good too.
And at no less she's
going to have to remain
on the immunosuppression.
She's an exceptional patient.
She was somebody who had
a very rare condition
and she was already
on immunosuppression.
So this is not something
that's going
to be widely performed
in the near future.
That still leaves
us asking questions
about how we can
replace complex organs.
Okay so here's the Prometheus.
There're actually two Prometheus
and this is the first myths.
This is about animation.
Animal means soul and it's
about bringing soul into things.
And the first story about
Prometheus is that he used clay
to create people and was
able to make them move.
And by making them move
that generated the soul.
Movement and soul were
closely related to one another.
And the more senior gods
were quite annoyed about this
because they felt it was their
place to decide who lived
and who died and so they
were pretty irritated but not
as irritated as they were
later on, as you will find.
So Prometheus, I
guess, he started to,
the legend of Prometheus
led on to things
like Mary Shelley's,
The idea that you could
create things from dead things
and make them move
and give them spirit.
And it's a good story.
Okay this is Anthony Atala.
Anthony Atala is the head of
Wake Forest University Institute
of Regenerative Medicine
and around 2000 he started
to apply tissue regenerative
to rebuilding bladders
in babies born
without sufficient bladders.
And he used collagen scaffold
to seeded them with muscle cells
and with epithelial
cells so not stem cells,
although if you grow these
things in culture, what you tend
to grow out in culture are
not the totally mature end
point cells.
They're what you call
progenerative cells.
They're cells which have
moved on quite a lot
from being stem cells
but they're not fully
differentiated cause those are
the ones that tend to be
selected out by culture,
slightly more potential.
Nonetheless, those were
the ones that he was able
to seed these scaffolds with
and implant these new bladders
into babies born
without bladders.
Previously babies with
bladder agenesis were reliant
on uroscopys so they're
having to basically pass urine
into bags for the
rest of their lives.
Now actually the first time
this was done it worked
for a bit and then didn't work.
The second time it
worked for a bit longer.
The third time it
worked for a bit longer.
It's actually been many years
before Tony Atala's group have
really got this right.
And that's a very
important lesson.
People have worked in heart
transplantation for many years
in the states, particularly
in Boston,
and they've invested vast
amounts of money in it.
And then a young trainee
from south Africa visited
for three months and said well
we're not gonna get much further
just by going around in circles,
asking the same questions,
asking new questions, asking new
questions, we're never gonna be
at the perfect point to put
these hearts into people.
He went back to south
Africa and did it.
And the first time Christian
Vonhoff did a heart transplant,
the patient died.
Now he might well have died
anyway, probably would have.
The second time the
patient lived a bit longer
and the third a little
bit longer.
But it was many, many
deaths before they got heart
transplant right.
Likewise with Tony Atala's
bladders, it took a long time.
Now the reason I mention this
is that there's a lot of hype
when you, and you'll hear
some stories in a minute
about the patients we've done,
a lot of hype when you hear
about patients receiving a
new this, that or the other,
made from this, that or
the other but coming off
from the hype there has
to be a degree of realism
and that it does take many,
many years and there needs
to be a great deal
of balance in the way
that things are reported,
the way that things are
presented to society.
And also in the expectations
this raises too.
And commonly it's the
partnership between surgeons
and scientists that are really
gonna take things forward.
Nonetheless, Tony Atala is
inspirational and by looking
at his work, reported
some years on by the Times
but good [inaudible] we felt
actually this was a good
prospect for rebuilding
airways too
that we could do
something similar.
And so with a colleague of mine,
Professor Macarenian [phonetic]
in Spain, we worked from
using stem cells in pigs
to rebuild the trachea, the
trachea is the windpipe.
It's actually probably the
simplest thing you could
probably start with, if you
wanted to rebuild an organ.
Technically it's
kind of an organ
but it might be regarded
as a tissue.
All it has to do is
conduct air one way
and mucus the other
so very simple tube.
It's also very thin so its
demands, in terms of oxygen
and nutrients, are
fairly limited.
But it's bound by chemical
properties that we'll describe.
So as a starting point
for rebuilding things,
we thought it was a
good place to start.
And we got some good
results in pigs.
Regenerative medicine, so
as I said at the beginning,
it's a very sexy thing
and it's a new thing.
But actually it's not that new.
When I took my entrance exam for
university, the question was all
about the prospects
for gene therapy.
That was a long time ago.
And these days we're just
about seeing the real products
of gene therapy coming
through in really striking
and helpful ways so great
work being done at Moorfields,
for example, where they
are now able to cure people
with certain congenital
inherited forms of blindness,
spectacular results but
it has taken 20 odds years
to get to that point.
So it's not new,
nor is biology new,
nor is stem cell biology new
or biomaterials, none is new.
What's new is the appreciation
that by working together
in large multidisciplinary teams
across institutions frequently,
you can actually get something
which is much greater
than the whole.
And by willingness in
society and regulators
and medical systems, to accept
firstly manned procedures,
we're able to actually start to
get these things into patients
at an early stage than we
previously thought possible.
So it's the team building.
But also the recognition that
we need to go back repeatedly
from clinic to scientist
to answer questions raised.
So it's teams and it's not
new but it is very exciting.
This is a windpipe
or section thereof.
This is a bioreactor.
Bioreactors are simply
boxes in which you do stuff.
Again, there's a lot of
hype around bioreactors
but that's all they are.
You can have little tiny ones
or you can have great
big enormous ones.
And here we have
bioreactors which we use
to take the cells
out of donor tissues.
What we don't want here
is the problems you have
with transplanted organs where
tissues are going to reject
so what you try and do is remove
those components of tissue
which would make it reject, in
particular the HLA molecules.
And so we use a combination
of washing with detergents
and enzymes, which is constantly
being refined as critical
to make it quicker
and more efficient,
and this removes
those components
of cells which make it reject.
And in our patients
we've not seen any signs
of rejection at all, so far.
So it's clearly affective
in that regard.
At first we thought it
would remove all cells
but it doesn't do that,
as I'll show you later.
And we do that in a bioreactor
and then you can take any cells
that you've grown and
put them on the scaffold
of the bioreactor before
you implant it in a patient.
And what you're left with is a
bit of tissue that looks a bit
like a dead organ really,
which is exactly what it is.
Now amusingly if you go
into Philip Ball's book you'll
see this illustration which is
of an alchemist from
about 500 years ago.
And what they were doing is
they took putrefied matter,
they took a bit of dead tissue,
commonly from the placenta,
in fact, and they would put it
in a dedicated container
in a culture medium.
In fact they would then rotate
it so that it was in air
and the culture medium
and frequently they would
have it one within another
so they would have two rotating
from another on the basis
that it was like the
celestial bodies rotating
around one another.
And the idea was that by doing
this you would regenerate
human beings.
In fact you'd make
these things, Homunculi,
which means little men,
which is what I am.
And you can see a
little man in there.
He's got more hair
than I've got.
I put this out because
again there's
so much hype around this.
We all think we're so clever.
We know so much about
science and technology
so we're very excited.
But perhaps in 500 years
people will look back
at what we've been doing
and be just as amused
by the concept you can grow
little men in bottles like this.
And perhaps we're trying
to do the same thing the
Homunculi were doing.
And of course the placentas,
by the way, placentae,
are a very rich source of stem
cells so they were possibly
on to something, without
really knowing it.
Okay so we reached a certain
point in our pig studies
where we realized that if
you implant scaffolds alone,
you get to a certain level
but they don't tend
to survive that long.
They scar up.
If you put in epithelial
cells then they protect you
from infection.
And if you add chondrocytes,
you get a degree of rigidity.
The best thing is a combination
of all three and the pigs
who received all
three did the best.
In 2008 Palo [phonetic]
saw, my colleague in Spain,
saw a patient from Columbia who
had a stenosis of the airway
which had been treated in
lots of different countries
and really reached the
point where she was going
to lose one lung and
possibly both lungs
as a result of airway blockage.
So she did conventional
and was on the ITU a lot.
And we put it to her and to
the authorities in Barcelona
at that time, that's
where she was,
that we had reached
a certain point
in our preclinical experiments.
And this is technology which
we couldn't prove would work
but there was no
conventional technology for her.
And if she was willing,
would they be willing,
this clinical ethics
committees, to let us try?
And they were.
We in fact grew her bone marrow
stem cells here in Britain
and Bristol Wells at the
time and her epithelial cells
from her nose and from her
lungs in our labs in Bristol,
in a very Heath Robinson way,
in a way which now the MHI,
I'm sure, would not permit.
They did know about it
and did give us permission
to do at that time.
Having grown it all up,
we then flew it back
to Spain and implanted it.
So I'll just run this,
oh, hey, go back, go back.
There we go.
How many people have
seen this video before?
Yeah, you're the only one?
How many times have
you seen this video?
How many times?
So this is the stenosis of
the airway, very, very tight.
Because the surgeries
had shortened the airway,
it was pulling it up on the
aorta, the big blood vessel
in the chest, which is
further compressing it
and making it work
even less efficiently.
This is a donor trachea which is
from a car accident
victim in Catalonia.
The Catalonia transplant
authorities rapidly swung
into action.
They have an opt out
system in Catalonia.
They have far fewer problems
with transplant donors
that we do.
I know that discussion
is ongoing in the UK
at the moment, certainly
in Wales.
I think they're going to
introduce it down there.
So we took epithelial cells
and bone marrow stem cells.
It just so happens
serendipitously that one
of the labs along from me
was run by Anthony Hollander
who was an expert
in chondrocytes
and he's been working on
differentiating stem cells
into concepts for many
years with the idea
of replacing knee joints
and hopefully he'll be
able to help [inaudible].
So serendipitously we already
have protocols for doing this,
for making MSCs,
Mesenchymal stem cells,
grow out into chondrocytes.
And we're able to see
the outside of this
with chondrocytes and watch
them grow prior to implanting it
so we have monolads,
[phonetic] epithelial cells
and chondrocytes.
So we checked out Palo works
cause he's a very talented
surgeon, implanted that.
And she didn't need to be
ventilated post operatively.
She went home after 10 days.
She's working full time
looking after her kids three
and a half years down the line.
Now to say that it's all
gone perfectly is not true
and it would be absolutely
stunning if it had.
But it went extraordinarily
well, I have to say.
Now she had to have a short
stent put in, that something
to hold her for a six
month period, for stenosis
at the proximal end of the
graft and that has now recurred.
But she only needs that
stretching up with a balloon
which can be done endoscopically
once every six months
so it's really not that
bad and certainly no worse
than anybody who's
had a lung transplant
who needs similar dilatations.
That's something we need to
look at about why she developed
that stenosis and we need to ask
careful questions about that.
But the rest of the
graft is healthy.
Then in 1999, sorry
2000, I was approached
by Martin Elliot who's the
Cardiothoracic Surgical head
at the Great Ormond
Street, about a patient
that they had just seen
and had been referred
down so this child was born with
a very tight stenosis and also
with some congenital
cardiac defects and had
to have major surgery at
birth and had the form
of reconstruction that was used
at that time, which was a kind
of [inaudible] to care,
really but that kind
of kept him alive
and held things open.
As he grew, at age 2 he
had a bleed where the stint
that was holding him open
eroded into a blood vessel
so that all had to be redone.
But between the age of 2 and
the age of 10 he was okay,
albeit held open by
more metal stints.
There are meshes of metal which
you can insert into the airway
and as the child grows
you can put balloons
down and make them bigger.
However over time these
metal stints erode
through the wall
and can pass it.
They can go beyond it.
He came down to breakfast one
day in Belfast and coughed
and blood started
pouring out of his mouth.
He eroded into his
aorta, we found.
Happily it clotted off.
He went to Belfast
[inaudible] and was flown
to Great Ormond Street
and stabilized.
What we didn't have
here was time.
We didn't have a
lot of time we had
to plan [inaudible]
separation in this case.
And so we used a
modified protocol
and literally threw
a protocol together
for which you can
certainly criticize some
of the things we did and I
will go into that in a minute.
At long last we were able to
get an off the shelf scaffold
which we retrieved earlier
for experimental purposes
and recellurize it
in the operating theatre using
his own bone marrow stem cells
which were not differentiated
to chondrocytes.
They're just taken straight
out of the bone marrow,
sent up to the role
free self therapy labs
where they separated down
to an NSC rich fraction.
I have to say we
did have a few days
so we'd actually given him
a cytokine called G-CSF
in the meantime which
boosts your production
of bone marrow stem cells.
So we had an enriched fraction
which was then transported back
to the operating theatre
where his heart operation
was ongoing under bypass.
Monty Elliot, a very
skilled surgeon was able
to prepare the aorta and we
then poured the bone marrow stem
cells over this graph
in the operating theatre
and added some cytokines too
which we thought
might be helpful.
And that wasn't a
complete guess.
This is based on protocols
which are in clinical use
for regenerative meds and
purposes for skin regeneration
and bone regeneration
in Germany at that time.
And in particular[inaudible]
which is known
to induce chondrogenesis
and autologous
if it's left to progress.
And also something called EPO,
which I'm sure you've heard,
EPO boosts your red blood count
and stuff and EPO is known
to induce autologous and help
support new blood vessel growth
so both of these are
licensed to use in man
and there was a good
rationale for using them
so we squirted them on to
the graft and we continue
to get an EPO every other day
for a few weeks afterwards.
This was implanted
and it worked.
It saved his life, essentially.
We also put in a new sort of
stint because we wanted a stint
that was not metal and so we
used an experimental stent
which we developed in the Czech
Republic to keep this open.
So that was March of last
year and it saved his life.
But he has not had an
uncomplicated course since then.
In particular he was in the
hospital for about three months,
oh sorry, I thought
somebody else fainted.
[laughter] I'll skip over that.
He was in the hospital for about
three months for some reasons,
which I'll show you in a minute.
He had a lot of endoscopies
to keep the airway clear.
Subsequently he went home,
he went back to Belfast
and he was well enough to be
on Irish national television
at Christmas playing the drums.
And you can actually
look that up.
He's called [inaudible]
if you want to look it
up on international
television and he's gone back
to school in the new year.
He also has grown in height,
grown in weight and he's coming
into the hospital less
and less frequently now.
So his white count went right up
and that might have caused
some issues, actually.
This is, the first problem we
encountered was this influx
of very dense secretions
that we'd never seen
in an airway before.
We sent it off.
And in fact what this turns
out to be is something
called DNA net,
these are a neutrophil
entrapment traps
and basically they're
produced by dead neutrophils
for dead neutrophils
to capture bacteria.
And nobody has ever
reported seeing
such a large quantity of this.
Now of course we boosted
this kids white count.
He's got a raw surface and he's
also got this irritating stint
in the way.
And we think it's this
combination of factors
which induced this
incredible tenacious material
that needs sucking out every
few days for weeks on end,
something we definitely
want to avoid in the future.
We did find that DNA
treatment, however, helped that.
And this is what it looked
like about three months
so it's all starting
to heal over now.
He's still got the
stint in place
which we think was also
causing a lot of problems
in granulation tissue
and we certainly would
not use this form
of stint again in the future.
And this is what it looks
like about six months ago.
It looks better now.
So it's now got a complete
covering of epithelium,
much of which but not
all of which is ciliated,
that is it's got these
cilia to help things move.
So he now has an airway.
It is epithelia.
One thing that was never
a problem is autologous.
All of the grafts
we put into animals
or people have rapidly developed
blood supply within about five
to seven days so that you
get so vessels really do go
into these things very
quickly and for reasons
which I hypothesize are
related to the content.
Here this was just a proteomic
analysis of the HDH showing
that it probably was DNA nets.
That is a normal trachea.
That is the trachea that we
took out, which was horrible.
This is decellurized trachea.
So this is what decellurized
material looks like.
It's got not cells there but
you still see little black dots,
these lacuna here so
there's probably little bits
of cells left behind.
We checked for the presence of
DNA, which is very irritant,
so we make sure we've
washed away the DNA.
But it's very likely there
are bits of cells left behind.
It's not completely
acellular in that sense.
And these are ciliated cells
which you can never see
on the surface so he's
now got the ciliates
that we wanted there
in the first place.
We also subjected the
scaffold to proteomics
and this was really,
really interesting
because we pulled out, if you
apply proteomics to a number
of these scaffolds, it's been
very difficult to do this
up until now because there's
so much collagen dominating
the protein content
of these scaffolds that
actually really drilling
down to smaller molecules,
present in small quantities
of have been actually difficult
but the most modern machines
you can't do that now.
You can get rid of the masking
effects of the huge weight
of elastin collagen and
see the other stuff.
And it's really interesting
because you can group them
into molecules which are likely
to really help these grafts
in many ways and
antigenic molecules,
things which effect immunity,
things which affect stem cell
migration, differentiation
and a whole host
of other things.
And of course they might
have adverse effects as well
as positive effects and this is
going to be a really interesting
of research for the future
that we at UCL are actually
at the cutting edge
of, working out which
of these molecules really helps.
And this is really very
important as we go forth
because what we'd like to do in
the future is not have to rely
on organ donors for this as well
but to be able to use some form
of synthetic grafts and maybe
a combination of synthetics
and biologics might be a
way to go in the future.
So we started using material
from past PCU developed
in the division of surgery and
March of this year it was put
into a patient in Sweden
and in October we put this
into a patient at UCLH, a
totally engineered trachea made
from past PCU decellurized
in exactly the same way
so that we could do
the decellurized graft.
And the advantage to use
this material that it's going
to have biochemical
rigidity, sort of rigidity
that we do not see for
a long time in Karen
and that was a problem
in Claudia too.
So you can get that
but getting the cells
to stick is a big issue, getting
angiogenesis is a big issue.
If we could understand which of
those molecules that we now find
by those pro [inaudible]
techniques, are really important
in getting angiogenesis
and cell growth
in our decellularized
biological scaffolds.
Then perhaps we could
decorate our synthetics
to make them intelligent
and then we'd have the
best of both worlds,
something off the shelf that
we could put into people
that would do the
things we need it to do.
This is the synthetic scaffold
going into the patient in UCLH
in October and she's doing fine.
She's back home in
Brighton, in fact.
And that's the first time
anybody's had the complete
trachea replaced.
There's some brilliant
surgeons here.
One of the wonderful
things about working
at the biggest bioactive
university in Europe is the fact
that we're also linked to some
of the biggest hospital
groups as well.
And you can go around and build
a team of scientists, doctors,
surgeons, engineers, experts
in business, by walking a mile
from where you're sitting,
you can build world customs
and really I don't believe
we could have delivered this
as quickly as we did for this
desperate patient anywhere else
in the world.
I generally don't believe it.
That's Claudia who's
well to this day
and that's Karen
who's still smiling.
So that's great and
it's wonderful hype
and it's very heartwarming
but they are one-off's.
So let me take you
back to Anthony Atala
and indeed to Christian Vonhoff.
One swallow does
not a summer make.
We need to do a lot more.
We've been able to do these
because you can do one-offs
under exceptional circumstances
where patients are
desperately ill.
You can do it under what's
called a hospital exemption
certificate and you
can prepare materials
under what's called
a specials license
in specially credited
so the minute you say okay, we
now need to do five of these,
it becomes a clinical trial.
And as soon as it's a clinical
trial and these things count
as drugs, you're then into
the whole regulation framework
necessary to credit a drug.
And we don't have big
pharmaceutical companies
behind us.
So it then becomes difficult
to translate these one-offs
into bigger numbers.
It's something that all
countries are grappling
with right now.
And by working with
our regulators,
I think we're actually starting
to get somewhere on this
so we hope we will have the
first trials going of this
in about 18 months
time, we hope.
And in the meantime we're
still in the position
to do one offs incrementally
improving as we go.
But we need time as well.
Six months reporting, as in
Claudia's case, is not enough.
We've seen her develop
stenosis very recently.
We don't know what
she's going to be
like in another year's time.
We need plenty of time.
And there are other
potential complications
of using stem cells.
We don't know that Claudia's not
gonna develop some kind of tumor
because we've stuck
stem cells into her.
It's extremely unlikely,
first of all
because we've followed her
for a while anyway but also
because MSC's, Mesenchymal stem
cells have an extremely high
safety profile.
They've been used in something
like 10 to 20,000 patients now
for hematological disorders
around the world and none
of them have developed
any malignancy
so we believe we're dealing
with something very safe.
But we need time to see
how these things work,
time and numbers.
This is a decellurized
larynx, one that I'd very much
like to be able to put one of
these in but it's very thick,
unlike the trachea,
angiogenesis is not going
to support the whole thing,
which is why we're now working
on ways of decellularizing
by using their own
vascular supply.
Here what we're gonna end
up with is something that's
like a transplanted organ
that's been decellurized
through its own vessels
so you can sew those
same vessels back
into the body again.
So in effect, it's
like a transplant
but it ain't gonna reject.
And in fact what you find
here is that if you do this,
all the blood vessels, down to
the level of small capillaries,
retain their basement
membrane so they don't leak.
You get no leakage.
And they're circulating
endothelial angiogenesis cells,
which line these vessels
very quickly and allow it
to support [inaudible].
Now this is a piece of bowel,
actually making the
complex epithelial necessary
to make a functioning bowel.
This is another matter
But we potentially have a way
of building organs this
way and making them.
Now this is very
exciting work being done
at Great Ormond Street.
We are now in a position
to identify congenital
in kids a lot earlier
than before,
using various screening
And sometimes you have months
before a baby is born before
and you can plan for.
Unfortunately some
of the abnormalities are
presently incompatible
with life, especially
airway problems,
kids born without a
trachea can't survive.
Now actually amniotic fluid is
a very rich source of stem cells
and now very versatile
stem cells
and of course they're the same
stem cells that HLA as the baby
so that the baby
has stem cells too.
You can retrieve this some
months, if necessary, antepartum
and in theory you can use that
to seed onto the scaffold.
You can build an
organ in preparation
for a baby being born.
And we have an operating
theatre at UCLH
where you can do something
called exit procedures which is
where the baby can remain attach
to the mum, who is under GA,
be delivered by cesarean
section and you can operate
on the baby prior to
developing the placenta
so you've then got
complete freedom.
This is done for heart
surgery at the moment
but we believe we could probably
do it for airway surgery too.
And it's now kind of
a race between Harvard
and Great Ormond Street
to see who is going
to be able to do this first.
Palo is the surgeon, he's
brilliant, brilliant man.
A surgeon who actually
does understand stem cells.
So you should be
asking him next time.
Okay, here's Prometheus
again, who in a way turned
out to be even naughtier
than creating humans,
having created them he
then gave them fire.
And this gave him enormous
power and independence.
The kind of power and
independence the gods really,
really didn't want them to have.
And so they were
pretty pissed off.
And so what they did was
they changed into a rock
and they had an eagle pick
out his liver every
day for eternity.
[laughter] Which is a
bit rough, isn't it?
It's a little harsh.
By chance, whether they
knew it or not, of course,
livers have a great
capacity for generations
so actually it's interesting
that they should choose that.
Here we have Jeremy Brockes at
this university who specializes
in studying regeneration
and he's worked on the genes
that are responsible for newts
regrowing their limbs and so on.
He tells us that unfortunately
humans don't have the analogs
which would allow us to
regrow limbs in the same way
that newts will but nonetheless
there may be parallels in some
of that work which allows us
to better understand
intrinsic regeneration.
Okay so we're not the
only ones in this field.
There's a lot of other people
and this was some exciting work
that came out of
Boston last year.
How do you build a lung?
Well you actually do exactly
what we've done for the trachea
but we do it with a
lung, is the answer.
And here they did it for a rat
and they actually created
some really nice looking lungs
which were able to support
this rat for eight hours.
It was operating in the
rat for eight hours,
which I think is quite
impressive actually.
So that's something you can
do by decellularization,
recellurization with
stem cells here
for [inaudible],
keep them alive.
But we have huge numbers of
challenges still ahead of us.
We need to bridge this funding
gap, which is still present,
of course, the weight
of regulation.
So these issues have just been
talking about how to do you get
from one-offs in animals
into human beings,
which is very complex.
And none of the big funding
are dipping their toes
in the water at the moment.
The small regenerative medicine
companies trying to take
on one product at a time but
right now in a global recession
and with no certainty that these
very expensive products are
really gonna make it, it's
extraordinarily difficult.
We need to also manage public
expectations, as they say.
Remember my entrance exam?
Okay it was 1979.
It was about the prospect
of gene therapy and now
in 2011 we're really
seeing it happen.
So we're talking about it now
and it may be 20 years
before we're really starting
to replace organ transplantation
with these things.
This is Chris Reeve who,
I'm sorry the font changed.
I don't like this font.
Chris Reeve who, as you know,
had a severe spinal cord injury
and he was a great proponent of
the application of stem cells
or exploration of stem
cells in any case.
Because George Bush's regime
were ridiculously anti all stem
cells, they just didn't get it.
That actually most research
is not embryonic stem cells,
it just isn't.
He lobbied and lobbied and
he lobbied successfully
with California so
[inaudible] $30 billion
of California taxpayers
money and put
in a bonus that's protected
and that's equivalent today
to the state debt of
California but they can't get it
and it's protecting
the stem cell research.
Unfortunately he passed away one
month before that was approved.
And he said so many of our
dreams seem impossible.
Then they seem improbable.
I think at this stage we're
at the improbable stage.
I mean I'd love to say that
you know we've really got it
with airways and now we're
going to move on to esophagus
and now we're going to move on
to heart and lungs but I can't
in all honesty say that.
What I can say is we've
made some great strides.
And there's absolutely potential
for us to use these kinds
of technologies to replace
organs in the future.
At least sometime in the
world we hope it will all
become inevitable.
There's an awful
lot of people here.
You've helped us do all this.
Closing comment is from
Brenda who was a recipient
of laryngeal transplant
last year.
She's very happy.
She can talk to her
grandchildren for the first time
and she's extremely happy.
And she said at a
press conference,
I don't know what the future
may bring but it's sure better
than what we left behind.
And I'm sure that's true
also of transplantation
and stem cell technologies.
I don't know what the
future is gonna bring
but I think it's gonna
be absolutely better
than what we've got at the
moment with transplantation.
Thank you.

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