Prometheus and I: building new body parts from stem cells (15 Nov 2011)

Uploaded by UCLLHL on 18.11.2011

>> 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, Frankenstein.
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 techniques
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, cells,
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 treatments
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 scaffolds
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 laboratories
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 organs
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 altogether.
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 abnormalities
in kids a lot earlier than before,
using various screening techniques.
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.