Siddharthan Chandran: Can the damaged brain repair itself?

I'm very pleased to be here today

to talk to you all about how we might repair

the damaged brain,

and I'm particularly excited by this field,

because as a neurologist myself,

I believe that this offers one of the great ways

that we might be able to offer hope

for patients who today live with devastating

and yet untreatable diseases of the brain.

So here's the problem.

You can see here the picture of somebody's brain

with Alzheimer's disease

next to a healthy brain,

and what's obvious is, in the Alzheimer's brain,

ringed red, there's obvious damage -- atrophy, scarring.

And I could show you equivalent pictures

from other disease: multiple sclerosis,

motor neuron disease, Parkinson's disease,

even Huntington's disease,

and they would all tell a similar story.

And collectively these brain disorders represent

one of the major public health threats of our time.

And the numbers here are really rather staggering.

At any one time, there are 35 million people today

living with one of these brain diseases,

and the annual cost globally

is 700 billion dollars.

I mean, just think about that.

That's greater than one percent

of the global GDP.

And it gets worse,

because all these numbers are rising

because these are by and large

age-related diseases, and we're living longer.

So the question we really need to ask ourselves is,

why, given the devastating impact of these diseases

to the individual,

never mind the scale of the societal problem,

why are there no effective treatments?

Now in order to consider this,

I first need to give you a crash course

in how the brain works.

So in other words, I need to tell you

everything I learned at medical school.

(Laughter)

But believe me, this isn't going to take very long.

Okay? (Laughter)

So the brain is terribly simple:

it's made up of four cells,

and two of them are shown here.

There's the nerve cell,

and then there's the myelinating cell,

or the insulating cell.

It's called oligodendrocyte.

And when these four cells work together

in health and harmony,

they create an extraordinary symphony of electrical activity,

and it is this electrical activity

that underpins our ability to think, to emote,

to remember, to learn, move, feel and so on.

But equally, each of these individual four cells

alone or together, can go rogue or die,

and when that happens, you get damage.

You get damaged wiring.

You get disrupted connections.

And that's evident here with the slower conduction.

But ultimately, this damage will manifest

as disease, clearly.

And if the starting dying nerve cell

is a motor nerve, for example,

you'll get motor neuron disease.

So I'd like to give you a real-life illustration

of what happens with motor neuron disease.

So this is a patient of mine called John.

John I saw just last week in the clinic.

And I've asked John to tell us something about what were his problems

that led to the initial diagnosis

of motor neuron disease.

John: I was diagnosed in October in 2011,

and the main problem was a breathing problem,

difficulty breathing.

Siddharthan Chandran: I don't know if you caught all of that, but what John was telling us

was that difficulty with breathing

led eventually to the diagnosis

of motor neuron disease.

So John's now 18 months further down in that journey,

and I've now asked him to tell us something about

his current predicament.

John: What I've got now is the breathing's gotten worse.

I've got weakness in my hands, my arms and my legs.

So basically I'm in a wheelchair most of the time.

SC: John's just told us he's in a wheelchair

most of the time.

So what these two clips show

is not just the devastating consequence of the disease,

but they also tell us something about

the shocking pace of the disease,

because in just 18 months,

a fit adult man has been rendered

wheelchair- and respirator-dependent.

And let's face it, John could be anybody's father,

brother or friend.

So that's what happens when the motor nerve dies.

But what happens when that myelin cell dies?

You get multiple sclerosis.

So the scan on your left

is an illustration of the brain,

and it's a map of the connections of the brain,

and superimposed upon which

are areas of damage.

We call them lesions of demyelination.

But they're damage, and they're white.

So I know what you're thinking here.

You're thinking, "My God, this bloke came up

and said he's going to talk about hope,

and all he's done is give a really rather bleak

and depressing tale."

I've told you these diseases are terrible.

They're devastating, numbers are rising,

the costs are ridiculous, and worst of all,

we have no treatment. Where's the hope?

Well, you know what? I think there is hope.

And there's hope in this next section,

of this brain section of somebody else with M.S.,

because what it illustrates

is, amazingly, the brain can repair itself.

It just doesn't do it well enough.

And so again, there are two things I want to show you.

First of all is the damage of this patient with M.S.

And again, it's another one of these white masses.

But crucially, the area that's ringed red

highlights an area that is pale blue.

But that area that is pale blue was once white.

So it was damaged. It's now repaired.

Just to be clear: It's not because of doctors.

It's in spite of doctors, not because of doctors.

This is spontaneous repair.

It's amazing and it's occurred

because there are stem cells in the brain, even,

which can enable new myelin, new insulation,

to be laid down over the damaged nerves.

And this observation is important for two reasons.

The first is it challenges one of the orthodoxies

that we learnt at medical school,

or at least I did, admittedly last century,

which is that the brain doesn't repair itself,

unlike, say, the bone or the liver.

But actually it does, but it just doesn't do it well enough.

And the second thing it does,

and it gives us a very clear direction of travel for new therapies --

I mean, you don't need to be a rocket scientist

to know what to do here.

You simply need to find ways of promoting

the endogenous, spontaneous repair that occurs anyway.

So the question is, why, if we've known that

for some time, as we have,

why do we not have those treatments?

And that in part reflects the complexity

of drug development.

Now, drug development you might think of

as a rather expensive but risky bet,

and the odds of this bet are roughly this:

they're 10,000 to one against,

because you need to screen about 10,000 compounds

to find that one potential winner.

And then you need to spend 15 years

and spend over a billion dollars,

and even then, you may not have a winner.

So the question for us is,

can you change the rules of the game

and can you shorten the odds?

And in order to do that, you have to think,

where is the bottleneck in this drug discovery?

And one of the bottlenecks is early in drug discovery.

All that screening occurs in animal models.

But we know that the proper study of mankind is man,

to borrow from Alexander Pope.

So the question is, can we study these diseases

using human material?

And of course, absolutely we can.

We can use stem cells,

and specifically we can use human stem cells.

And human stem cells are these extraordinary

but simple cells that can do two things:

they can self-renew or make more of themselves,

but they can also become specialized

to make bone, liver or, crucially, nerve cells,

maybe even the motor nerve cell

or the myelin cell.

And the challenge has long been,

can we harness the power,

the undoubted power of these stem cells

in order to realize their promise

for regenerative neurology?

And I think we can now, and the reason we can

is because there have been several major discoveries

in the last 10, 20 years.

One of them was here in Edinburgh,

and it must be the only celebrity sheep, Dolly.

So Dolly was made in Edinburgh,

and Dolly was an example

of the first cloning of a mammal

from an adult cell.

But I think the even more significant breakthrough

for the purposes of our discussion today

was made in 2006 by a Japanese scientist

called Yamanaka.

And what Yamaka did,

in a fantastic form of scientific cookery,

was he showed that four ingredients,

just four ingredients,

could effectively convert any cell, adult cell,

into a master stem cell.

And the significance of this is difficult to exaggerate,

because what it means that from anybody in this room,

but particularly patients,

you could now generate

a bespoke, personalized tissue repair kit.

Take a skin cell, make it a master pluripotent cell,

so you could then make those cells

that are relevant to their disease,

both to study but potentially to treat.

Now, the idea of that at medical school --

this is a recurring theme, isn't it, me and medical school? —

would have been ridiculous,

but it's an absolute reality today.

And I see this as the cornerstone

of regeneration, repair and hope.

And whilst we're on the theme of hope,

for those of you who might have failed at school,

there's hope for you as well,

because this is the school report of John Gerdon.

["I believe he has ideas about becoming a scientist; on his present showing this is quite ridiculous."]

So they didn't think much of him then.

But what you may not know is that he got the Nobel Prize for medicine

just three months ago.

So to return to the original problem,

what is the opportunity of these stem cells,

or this disruptive technology,

for repairing the damaged brain,

which we call regenerative neurology?

I think there are two ways you can think about this:

as a fantastic 21st-century drug discovery tool,

and/or as a form of therapy.

So I want to tell you a little bit about both of those

in the next few moments.

Drug discovery in a dish is how people often

talk about this.

It's very simple: You take a patient with a disease,

let's say motor neuron disease,

you take a skin sample,

you do the pluripotent reprogramming,

as I've already told you,

and you generate live motor nerve cells.

That's straightforward, because that's what

pluripotent cells can do.

But crucially, you can then compare their behavior

to their equivalent but healthy counterparts,

ideally from an unaffected relative.

That way, you're matching for genetic variation.

And that's exactly what we did here.

This was a collaboration with colleagues:

in London, Chris Shaw; in the U.S., Steve Finkbeiner and Tom Maniatis.

And what you're looking at, and this is amazing,

these are living, growing, motor nerve cells

from a patient with motor neuron disease.

It happens to be an inherited form.

I mean, just imagine that.

This would have been unimaginable 10 years ago.

So apart from seeing them grow and put out processes,

we can also engineer them so that they fluoresce,

but crucially, we can then track their individual health

and compare the diseased motor nerve cells

to the healthy ones.

And when you do all that and put it together,

you realize that the diseased ones,

which is represented in the red line,

are two and a half times more likely to die

than the healthy counterpart.

And the crucial point about this is that you then have

a fantastic assay to discover drugs,

because what would you ask of the drugs,

and you could do this through a high-throughput

automated screening system,

you'd ask the drugs, give me one thing:

find me a drug that will bring the red line

closer to the blue line,

because that drug will be a high-value candidate

that you could probably take direct to human trial

and almost bypass that bottleneck

that I've told you about in drug discovery

with the animal models,

if that makes sense. It's fantastic.

But I want to come back

to how you might use stem cells directly

to repair damage.

And again there are two ways to think about this,

and they're not mutually exclusive.

The first, and I think in the long run

the one that will give us the biggest dividend,

but it's not thought of that way just yet,

is to think about those stem cells that are already

in your brain, and I've told you that.

All of us have stem cells in the brain,

even the diseased brain,

and surely the smart way forward

is to find ways that you can promote and activate

those stem cells in your brain already

to react and respond appropriately to damage

to repair it.

That will be the future.

There will be drugs that will do that.

But the other way is to effectively parachute in cells,

transplant them in,

to replace dying or lost cells, even in the brain.

And I want to tell you now an experiment,

it's a clinical trial that we did,

which recently completed,

which is with colleagues in UCL,

David Miller in particular.

So this study was very simple.

We took patients with multiple sclerosis

and asked a simple question:

Would stem cells from the bone marrow

be protective of their nerves?

So what we did was we took this bone marrow,

grew up the stem cells in the lab,

and then injected them back into the vein.

I'm making this sound really simple.

It took five years off a lot of people, okay?

And it put gray hair on me

and caused all kinds of issues.

But conceptually, it's essentially simple.

So we've given them into the vein, right?

So in order to measure whether this was successful or not,

we measured the optic nerve

as our outcome measure.

And that's a good thing to measure in M.S.,

because patients with M.S. sadly suffer

with problems with vision --

loss of vision, unclear vision.

And so we measured the size of the optic nerve

using the scans with David Miller

three times -- 12 months, six months,

and before the infusion --

and you can see the gently declining red line.

And that's telling you that the optic nerve is shrinking,

which makes sense, because their nerves are dying.

We then gave the stem cell infusion

and repeated the measurement twice --

three months and six months --

and to our surprise, almost,

the line's gone up.

That suggests that the intervention

has been protective.

I don't think myself that what's happened

is that those stem cells have made new myelin

or new nerves.

What I think they've done is they've promoted

the endogenous stem cells, or precursor cells,

to do their job, wake up, lay down new myelin.

So this is a proof of concept.

I'm very excited about that.

So I just want to end with the theme I began on,

which was regeneration and hope.

So here I've asked John

what his hopes are for the future.

John: I would hope that

sometime in the future

through the research that you people are doing,

we can come up with a cure

so that people like me can lead a normal life.

SC: I mean, that speaks volumes.

But I'd like to close by first of all thanking John --

thanking John for allowing me to share

his insights and these clips with you all.

But I'd also like to add to John and to others

that my own view is, I'm hopeful for the future.

I do believe that the disruptive technologies

like stem cells that I've tried to explain to you

do offer very real hope.

And I do think that the day that we might be able

to repair the damaged brain

is sooner than we think.

Thank you.

(Applause)