Where Do I Come From? Royal Institution Christmas Lectures

This is an egg. But not just any egg.

The animal that will emerge from this can run

at 70 kilometres an hour and will live for over 30 years.

It's the world's largest bird, the ostrich.

But how can an animal so large and complex come from something so simple?

We all do it. We all begin life as a single cell.

And turn into...us!

But how do we do it?

This remarkable transformation

is one of the most exciting mysteries on earth.

It's life fantastic.

Have you ever stopped to think...

Have you ever stopped to think about how extraordinary you are?

Turn and look at your neighbour.

You're looking at them with your eyes

and their eyes are looking back at you.

How does that work?

How does your brain coordinate all that stuff?

Turn the other way and look at your other neighbour.

How did you just do that?

How did your brain know to coordinate all your muscles,

contracting, to turn your head, just when you wanted to?

You're amazing.

And you're amazing

and you're amazing.

In fact, we're all amazing.

We're all amazing because we're all hugely complicated machines

made up of, wait for it, 40 trillion cells.

Cells are the basic building blocks of life.

But can we imagine what 40 trillion of anything actually looks like?

MACHINE HISSES LOUDLY

Wow!

LAUGHTER

That was only 200,000!

If they were cells, that's nowhere near enough to make a person,

so we would need 200 million of these confetti cannons

to make 40 trillion pieces of confetti.

Or, put it another way. To see 40 trillion pieces of confetti,

we'd have to repeat an explosion like this once every second

for, wait for it, can anyone guess how long?

2,314 days.

That's about six years.

Where do all these 40 trillion cells come from,

and how on earth do they all know what to do?

Welcome to the 2013 Royal Institution Christmas lectures.

My name is Alison Woollard and I'm a developmental biologist

and today, you're coming with me on an adventure through life fantastic,

to see how these trillions of cells come together to make you.

So let's have a look at you.

I've got two of you here. Up here.

And I think you're in the audience this evening.

Can you identify yourselves?

Ah! Thank you very much. Come down, let's have a chat.

APPLAUSE

So, if you could just stand here so everyone can see how lovely you are.

Thank you very much. What are your names? I'm Chris. Kavita. Kavita.

Thank you for giving us your photos.

And would you confirm for us that these are in fact you?

And how old are you here? 13.

You're 13. And you're? 15. 15.

So this is you at 15 and you at 13.

OK? So what we're going to do now is, we're going to wind the clock back.

Do you want to come out a little bit further

so that you can see yourselves going backwards through your development.

The next picture will show what you were like when you were five.

Oh, that's very nice. I know. Was that your party? It was, yeah.

Very nice. Were those hats to cover your horns? Um, yeah!

Very nice. Were those hats to cover your horns? Um, yeah!

And you're looking very lovely as well, Kavita.

Let's wind the clock back again, 18 months. Aww! Really, really sweet.

And if you keep winding the clock back, let's go back again.

There you both are as newborn babies.

And, we can go back a bit further than that,

cos we can look to see what you were like,

this is when you were in your mums' tummies. 20 weeks.

About halfway through your development.

But, we can keep winding the clock back.

This is what someone like you would have looked like at about five weeks of development.

Does that look like you?

Have you got your Uncle Bert's ears?

I don't think so, not at the moment, no. Your dad's nose?

Hard to tell, isn't it? Let's go back again. This is four weeks.

Things are looking very different now, aren't they?

Let's go back again...

to a little ball of cells. Aw!

And back again, to this. This is where you all started.

This is a single cell.

An egg cell that's just been fertilised by your dad's sperm.

So, what would you say are the most complicated bits?

Where does the drama happen in your development?

Has it just happened at the age of 11-13, do you think,

or is it the earlier stages?

What would you say?

Probably the earlier stages. I would agree.

All the drama happens in those nine short months

of your early development.

Thank you so much for sharing your life history with us this evening.

Please go and sit down.

APPLAUSE

So how exactly does one cell, this one cell, for example,

become 40 trillion?

This bit isn't too complicated, actually,

because cells have the remarkable ability to split themselves

into two exact halves called daughter cells.

Funny, you know, developmental biology is very feminist.

We talk about daughter cells and mother cells.

We never talk about sons and fathers.

So, daughter cells.

And those daughter cells, in turn, can divide themselves in half.

And this carries on, so, shall we picture the scene?

I believe you've been trained with some glow sticks.

There should be one of you in row three, is that you? Yeah.

With a glow stick. What's your name? Eleanor.

Eleanor, thank you so much for agreeing to do this for us this evening.

You have one glow stick that signifies that first cell.

And your cell is going to, let's get it lit up, shall we? OK.

That's the way. Oh, they're nice and bright, aren't they?

So, what's going to happen is, I'm going to say "divide".

Does this sound familiar? I'm going to say "divide",

and you're going to divide,

so, you're going to go to the row behind, and the row behind that,

and the row behind that.

And that will show us what's happening as that first,

original cell starts to divide.

OK, ready? Divide.

And divide.

And divide again.

And divide.

Brilliant, fantastic.

We may have lost one or two cells along the way,

but it doesn't really matter.

We've ended up with 64, and we came from one,

and that all happened quite quickly, didn't it?

And, actually, if this lecture theatre was a bit bigger,

and we had a few more seats, so,

if we extended the lecture theatre out into Albemarle Street, by

the end of the 10th row, we'd have 512 of these glow sticks, or cells.

And, by the end of row 20, we'd have half a million.

And by the end of row 45, we'd have the 40 trillion lights,

or cells, that we would need to build a human.

So, you can see that the numbers get very quick, very quickly,

when we're talking about cells doubling.

And I don't know about you, but 45 cells doubling seems

like a relatively small number to get to 40 trillion cells.

Right, enough of all these numbers.

Let's look at some real cell divisions in some real organisms.

It's time to introduce you, ladies and gentlemen, to my hero organism.

And my hero organism is in this box. Really exciting.

Are you ready for this? Whoa!

What do you think? Huh? Impressed?

You don't look very impressed.

Because these are rotten apples. Would anyone like one?

No.

I wouldn't recommend it. They're a bit smelly.

Now, I don't work on rotten apples.

I work on something that lives in this box WITH the apples,

and likes to eat them. Do you know what that might be?

Anyone like to guess? Yes?

Bacteria, well, there's lots of bacteria in that box, yes,

but that's not what I work on. What about you?

Worms?

Sorry?

Worms? Yes! Brilliant! Worms.

Actually, a very small worm called Caenorhabditis elegans.

We call it C elegans for short. It's a nematode worm.

And actually, when we work on them in the lab,

we don't have big boxes of smelly rotten apples lying around.

We grow them on these nice, clean plates, these Petri dishes.

And if I hold this plate up to the light, and to the camera,

you should see some tiny, little white threads

about a millimetre long.

And those little, tiny white threads are the worms, C elegans.

And I'm going to hand some plates around to you now,

And I'm going to hand some plates around to you now,

so you can have a look, you can hold them up to the light yourself.

I've Parafilmed the plates so that you don't put your fingers in them

and get squishy worms all over them.

So they're very safe. So, let's just hand some of these plates out.

You can just pass them around, and have a look at your leisure.

Now, these worms are a little bit small, aren't they?

So, we really need some help to see them. We need a microscope.

And here's some microscopes over here.

And we're going to start by showing a video that we recorded

a little bit earlier on, of some worms crawling around on the plates.

So, here they are. Here's our C elegans. And here's Mum,

coming through the middle, looking a bit bossy.

And she has the babies all around her, so we can see

worms of different sizes. The little oval things are embryos.

They're the next generation of worms forming.

And we can see immediately how useful these animals are

because they're transparent.

And that means that we can see inside them.

And we can see all the cells in this animal.

There are about 1,000 cells altogether.

And, if you're a real geek, like me, you can

actually recognise each one of them. OK?

But it means that we can study development

by just looking at the animals very, very closely.

And these tiny worms have so much to tell us about the mysteries of life.

And I can see you thinking, "What's she talking about? They're worms.

"What does that, how does that tell us about OUR development?"

Let me show you something.

I want you to look at these pictures of embryos.

These are all embryos not very far into their development.

And they're all looking pretty similar, really, aren't they?

Well, let's reveal what they're going to develop into.

What are they going to... Wow! Rather different things. OK?

We've got a human, we've got a mouse, we've got

a sea urchin down there, and we've got my hero worm.

We just put a bit of DAPI stain in there,

to see the DNA of these worms.

But you can see that you get very, very different outcomes

from these rather similar beginnings.

And that's really useful to us, because it tells us that,

if we're interested in the development of

a complicated organism like ourselves,

or like the mouse, for example,

then we can look at these processes in much simpler organisms,

like worms and, because the processes of development

are quite similar, it's all about cells multiplying

and then working out what to do,

and going to the right place and doing it, it means that

we can study those processes in these very simple organisms,

and then apply what we learn to our own biology.

So, that's the power of model organisms.

And it makes sense to study worms, as they go through

these very similar developmental processes to us.

And yet, they develop much faster,

so we can see things happening much more quickly.

So, how fast? Can it happen right in front of us, right now?

Shall we create life, here, in the lecture theatre this evening?

Well, we can't create human life, but we can create worm life.

So let's get started.

My assistant, here, Peter has chosen for us some early embryos

and we are looking at them developing live in front of us.

So here, we have a two-cell embryo.

It's just gone through its very first division.

This is a really, really, really young worm.

And we're going to leave this running. It's our worm cam.

We're going to leave it running throughout the lecture,

and you'll start to see things happening to this.

And when something happens, I want you to tell me,

because I might not be looking at it properly.

And if you see something big happening,

like a cell dividing, just shout out,

and we can go back to it.

And we can also, we'll be recording, as well,

so we can go back and we can look at anything we might have missed.

And Pete, here, is going to keep score on his worm division scoreboard,

so, every time a cell divides, we're going to move on a number.

So make sure that you tell us when this happens, OK?

So, this is what gets developmental biologists like me

out of bed in the morning.

This is amazing because this is a new worm

being made right in front of us. OK?

You can't do that with a lot of organisms, but you can do it

with C elegans, because it's so easy to see this happening

under quite a simple microscope.

And we want to understand this amazing process.

How does an organism develop from an egg to an adult?

How is this controlled?

And how do our studies in these simple model organisms

shed light on our own development, and what can go wrong?

So, life, even though it's happening right in front of us,

it's little bit slow, and we've got a speeded up film to show you,

as well, to see what happens a bit later on

in the development of the worm.

So we've got one we prepared earlier.

And we can see all these cell divisions going on

and we're building up a ball of cells here, quite rapidly,

and then, what's going to happen is, that ball of cells is going

to reorganise itself into a three-dimensional thing.

to reorganise itself into a three-dimensional thing.

And we can see that start to happen. It's called morphogenesis.

That's the acquisition of form.

And you can see, this ball of cells has reorganised

itself into something that looks a little bit more like a worm.

And it's hard to see what's going on now

because the muscle cells in this one have started twitching,

because they've suddenly realised that they're muscle cells,

and twitching is what muscle cells do.

But we can see something now.

We're getting towards the end of the embryonic development stage,

and this is a little worm about to hatch out of its eggshell

and start its life as a worm.

So this tells us, then, that we are not just bags of disorganised cells.

So this tells us, then, that we are not just bags of disorganised cells.

In development, cells must cooperate to form tissues and organs.

They come together to make complicated bits.

Like this!

Now, this is not worm. This is a cow's leg.

I'm sure that this is quite obvious that this is not a worm.

And we can see all sorts of bits in here. We can see bone in the middle.

We've got muscle, here. We've got a bit of fat around the outside.

We've got connective tissue.

They've removed the skin, but we can see all these things.

We can see some blood, here, dripping away.

So, this tells us, then, that we only have to look inside one

bit of a body to see that it's composed of lots of different bits.

And, all these bits, all these cells, are doing different things,

And, all these bits, all these cells, are doing different things,

but they're all doing it in the right pattern.

In order to make this whole limb that works properly.

Thank you very much. Time to go and put that in the oven, I think.

Let's look at some more examples of cells working together in harmony.

I think Hayley, here, has got something else to show us.

Hayley, thank you for coming. What have you brought for us?

Shall we have a look? Yes, please.

Gosh! What's that? Let's have a look.

Does anyone know what that is?

Yes? Shout.

AUDIENCE: A heart!

Gosh, you're all very good, aren't you?

This audience, all very bright, I can tell.

So, yes, that's a heart.

What are you doing, putting it...? That's the dorsal aorta.

So, the heart is a pumping organ.

Very important for pumping blood around our bodies

so that it delivers oxygen to all of our tissues.

And the average heart beats 100,000 times a day.

No wonder we're all tired when we go to bed at night.

That's more than 35 million times a year.

Thank you, Hayley. What's that in the middle, there?

Ugh! Goodness me. What's that?

Let's see. Hold it up. Let's have a look.

Does anyone know what this might be?

Yes, shout at me.

AUDIENCE: Lungs. Lungs, yes!

It's got a funny little pipe sticking out of it.

We're going to use that in a minute.

But, the lung is an inflatable organ that you breathe with.

It has 1,500 miles of airways in it.

That's the distance from here to beyond Rome, OK?

And it has a huge surface area.

So, if we spread out this lung, so we used all its surface area,

it would take up about half a tennis court.

OK? In fact, I can't resist it.

We're going to have to blow it up, we're going to have to inflate it.

Can I have a volunteer to help with this?

Yes, would you like to come down? Thank you.

Right.

OK, put those on.

Don't I get any safety glasses?

What's your name? Tom.

Right, could you turn round so everyone can see how lovely you are?

Now, Tom, I'm not going to ask you to put any tubes in your mouth

and blow, because the chances are, you might suck as well,

and that wouldn't be good!

What we do have is a nice little pump here.

That you should be able to use.

Are we good to go, Hayley? Right.

Not too heavy.

Not too heavy, right. We have a bit of a...

With your foot, I think. Yeah, with your foot. See what happens.

Oh, it's going. Keep going. Can everyone see that?

Oh, it's going. Keep going. Can everyone see that?

Give it a few rapid bursts.

Yes, we're inflating our lungs. Look at that. We're inflating our lungs.

You're very good at this, aren't you? Inflating our lungs quite well.

Thank you, thank you so much for doing that.

If you'd like to go and sit down. Thank you very much, Tom.

And what's the final organ we've got here today? I can't guess. Ooh!

Ah, yes! Let's have a look at this. Does anyone know what it is?

Yes, shout.

AUDIENCE: Brain.

AUDIENCE: Brain.

Whose brain is it?

Did anyone donate their brain this evening? You did, did you?

Brains are in charge of everything, so they're full of neurons

that connect with each other and help us make decisions

about everything that we do.

So, all of these organs look... Thank you, Hayley, that's brilliant.

All of these organs look very different,

and they have very different jobs.

They're all composed of cells, aren't they?

So cells must look quite different from one another

in order for these organs to look at one another,

so let's have a look at some cells, shall we?

The first cell type we're going to look at,

does anyone know what these are?

Ooh! Yes, what do you think?

Nerve endings?

Nerve endings? Yes.

Neurons.

Neurons, yes. Why do you say that?

Because, they were long and spindly and had lighty-up sort of blobs.

Yes, and that's because they form these intricate connections

with each other and with muscle cells, and so on.

And that's absolutely crucial for our brains to work

and our nervous systems to work.

So neurons are really beautiful cells, and that's their job.

Let's have a look at the next cell type.

Now, does anyone know what these might be?

Yes? Blood cells?

Sorry? Blood cells? Well, actually, there are some blood cells on here,

but they've kind of sneaked on.

We have got some blood cells in there, yes.

INAUDIBLE RESPONSE

They're ciliated, well spotted. Biologist in the making over there!

They're actually lung cells. Does anyone have a cold at the moment?

Are you doing a lot of coughing? Are you coughing up loads of gunk? Yes?

Well, your using your lung cells a lot.

Because your lung cells have these hairs, these cilia, in them,

that act as kind of brooms, and sweep all the gunk

and all the phlegm along so that you can cough it all out of your lungs.

So, a very useful cell type indeed.

And the next cell type, the next cell type we're going to look at

is so special that it comes with its own handler.

Welcome, Beata, thank you for coming.

So, Beata, what have you brought for us this evening?

Oh, wow, look at them. Can we see those up on the screen now?

Can everybody see? What are these cells doing?

They're forming a big clump, but what are they doing together?

Can anyone see what these cells are doing together?

What's that? Yes? They're moving.

What kind of movement do you think it might be?

I thought they were pulsing.

Pulsing? Yes?

Er, beating?

They're beating! Excellent, well done.

So, what kind of cells do you think these might be?

Heart cells?

Heart cells, exactly, beating heart cells.

So, Beata, tell me how you got these cells to us this evening.

So, to make these cardiomyocytes,

So, to make these cardiomyocytes,

what scientists do is they use very young cells, called stem cells

and this is actually so young

that they can differentiate to any cell in our body,

so what we can do nowadays, we can instruct these young cells

to become cardiomyocytes,

when we use different factors and methods at the same time.

So, we've got these cells growing in a Petri dish,

nowhere near a heart, and yet they know that they should be beating

like heart cells, and they carry on doing that in their Petri dish.

I think that's amazing. How long will they do that for?

Probably for just a few minutes. Oh, just a few minutes.

We were lucky, then, weren't we?

And I can see that these might have some point in medicine.

Yeah, these cells are very important because these are very similar

to the cells that we've got in our heart, which means that

we can use them, for example, when we have got a heart attack,

so when the heart is injured.

Or also, we can use these cells to test new medicines.

Or also, we can use these cells to test new medicines.

We're just pausing for a minute to go to worm cam.

Because little worm embryo over there has done something exciting.

It's done another cell division, just about to.

This cell here is just about to split into two, and we can actually

see this cleared area here in the middle is the nuclei pulling apart.

This is happening, live. We didn't know that was about to happen then.

So, could you actually build a whole heart?

We hope that one day this will be possible.

However, there is more to a whole organ, like a heart, than just

the cells in a dish, as there are all very important

cells types in the heart as well, that play crucial roles.

But that would be amazing, wouldn't it?

Think what you could do to heart transplants

if you could grow hearts in the lab.

There'd be no queues for transplants.

And it would also mean that the patients who need a heart

could have a new heart grown for them from their own stem cells.

Another one's at it now, isn't it?

The other cell's starting to divide, yes.

So, things are happening in our worm.

Beata, thank you so much

for sharing these cardiomyocytes with us this evening.

Beata.

So, looking at all these different types of cell, then,

we can see how different organs might be generated.

But what is it that gives each different type of cell

its distinct properties?

What makes a neuron different from a heart cell?

Well, the answer to this is proteins.

It's the type of proteins that the cell produces.

And I can show you some proteins now

with the help of my special gestural interface machine here.

So, we can see that proteins on one level are quite simple molecules.

They consist of carbon, hydrogen, oxygen, nitrogen,

a bit of sulphur thrown in. Their basic units are amino acids.

There's 20 amino acids together.

But these are strung together completely differently

in different proteins,

and that gives all these different proteins a staggering

diversity in terms of their shape.

And I think I can get control of these proteins now

just by moving my hands, by trickery of modern technology.

And we can look all around these different proteins.

The first one I want to show you in detail is called myosin.

This is a protein that you find in muscle.

And if we look at it like that we can see that it has

a particular shape, that includes a tail.

And myosin is really important to help our muscles move.

And that's because this tail helps the protein do this job.

And the structure of myosin can bend and straighten itself, and this

bending and straightening creates the force required for movement.

So that's myosin.

The next protein we can look at here is called haemoglobin.

This is an oxygen-carrying molecule,

so it carries oxygen around the blood.

And the shape of haemoglobin is so important

because when one molecule of oxygen binds to the haemoglobin protein,

it actually changes the shape

and that encourages more molecules of oxygen to bind.

It's called cooperative binding.

And so you can imagine what an efficient

carrier of oxygen in our blood this is.

And so this is the reason why our different cells look

and behave in such different ways.

They all contain different shaped proteins.

In fact, this is one of the big secrets of life.

OK, enough of all these protein models.

Shall we see a protein in action?

Ollie, are you there? Thank you, come on down.

Ollie, would you just like to stand

and show the audience your wonderful machine?

I understand this is a vein viewer. Yes.

So we'll be able to view veins.

Shall we give it a go? Switch it on...

Can I have a look at your arm? Ah, here we are.

With this machine, we can actually look inside Ollie's body

without chopping him up, which is just as well, really.

Can you see that?

So, this is the blood inside Ollie's veins.

And this is an incredibly useful machine,

because when people are learning to take blood in hospital,

they can use this to see exactly where a patient's

veins are without poking them around with a needle.

So this is a really, really clever machine.

And what we're looking at here is this haemoglobin protein

that's rushing around inside Ollie's veins.

Shall we see if you've got any veins in your neck?

You should have, let's check.

There we are, lots of... Wow, you've got some big veins there.

Obviously a very oxygenated young man!

Yeah, brilliant! I think I might take this home with me.

Is that all right? Thank you very much. That is fantastic.

Would you like to go and sit down?

So we've been looking at blood in our veins.

Now let's see haemoglobin for real. This is a tube of pure haemoglobin.

It looks a bit brown and muddy, doesn't it?

That's because this is haemoglobin that doesn't contain

very much oxygen. It's not bound to oxygen very well.

In fact, in the body we would call it methaemoglobin.

And if you have too much of this kind of haemoglobin in your body

that's not good news, because you're not getting enough oxygen.

But what we can do in this experiment is oxygenate the haemoglobin.

So Sarah is going to bubble some oxygen through the haemoglobin.

We're going to get some bubbles, and what's happening here?

We're going to get some bubbles, and what's happening here?

Can anyone see a difference?

I've got a torch here to show the camera.

Can we see a colour difference there?

Yeah, quite impressive, isn't it?

It goes bright red and looks much more like blood.

So this is haemoglobin containing oxygen

and this is haemoglobin that isn't bound to very much oxygen.

And in us, that difference in that protein can be

the difference between life and death. Thank you very much, Sarah.

That's fantastic.

So haemoglobin makes up about 97% of the dry weight

of our red blood cells.

And so you can imagine how good an oxygen transporter our red blood

cells are, because they contain all this haemoglobin.

So this is a protein inside yourselves in action in you, now.

So, now we know that all our different tissues

and organs look and behave differently

because they're all composed of different cells,

and cell types can look and behave differently because

they contain different proteins, and proteins look and behave differently

because they're made of different combinations of amino acids.

So we've explained everything, haven't we?

Or have we?

What exactly is making all these different amino acids,

which in turn are making all the different proteins?

It turns out that the answer lies deep inside

each and every one of our cells,

and we're going to have to delve in very deep to find the answer.

We've looked at quite a few cells now, haven't we?

But what exactly is inside them? Let's take a look inside a cell.

So what we've got here is the cytoplasm,

which is jelly-like stuff, which contains bits and bobs,

like the mitochondria, which are the little pink things.

And they make energy in our cells.

And we've got the golgi apparatus, which are the little yellow

things, and they help to transport and sort proteins around the cell.

But look here in the middle.

In the middle is the nucleus, that's the blue bit.

The nucleus, the hub of the cell.

And the nucleus contains a very special substance indeed.

It was over 140 years ago, in 1869,

when a Swiss biochemist called Friedrich Miescher...

There's a picture of Miescher.

He extracted a substance from the nuclei of white blood cells.

Scientists had just discovered that cells were the basic unit of

life and Miescher was desperate to find out

about their chemical components.

about their chemical components.

So do you know how he got hold of his white blood cells? Ugh!

Do you know how he got his white blood cells?

Well, every morning, he went to the clinic

and picked up a load of these.

Because in the days before antiseptics...

..these were soaked in pus.

They really are pussy, aren't they? Ugh!

These were soaked in pus

and pus is a good source of white blood cells,

with their large nuclei, and these were the cells that Miescher wanted,

because he wanted to get in and find out what was in their nuclei.

Thank you, Clarissa.

So, Miescher added alkali to burst open the cells

and then he extracted a substance that he called nuclein.

And Miescher got really excited about nuclein because it was

unlike other biological molecules he'd come across.

It was an acid and it contained phosphorus.

Now, this was the first extraction of DNA, of course.

Nuclein turned out to be deoxyribonucleic acid, or DNA.

The most important molecule in the living world.

And the study of DNA is one of the greatest triumphs of modern science.

It's found in every living thing on earth. But what does it look like?

Well, let's make some.

So, Hayley here has been beavering away, making a sample for us

from some fish roe, so eggs, basically.

And this sample prep is halfway through

and she's going to finish it up now,

she's going to pour on the final solution and we should get some

nice, stringy DNA,

which I should be able to spool up

onto my forceps.

Let's see this...

Wow, it's very gloopy. Look at that!

Can you see these tiny threads of DNA in all this gloop?

Look at all this stuff! That's amazing.

Thank you very much, Hayley.

Thank you for showing us the stuff of life.

Now, let's fast forward from Miescher in 1869 -

when Miescher had first done the experiment

that we've just done - to the 1950s,

when techniques for determining

the structure of biological molecules were being developed.

James Watson and Francis Crick, working in Cambridge,

capitalised on the newly available data and expertise

and published the model of the DNA molecule that we know today.

And here is our very own Royal Institution version of this model.

One long molecule spiralling around in a double helix.

Exquisite, ordered, simple and regular.

Two strands of nucleotides,

each with a strong backbone composed of sugar and phosphates,

with what we call nucleotide bases on the inside.

Adenine - A,

guanine, or G,

cytosine - C,

and thiamine, or T.

And these bases always pair together according to some

simple rules. A always pairs with T

and C always pairs with G.

These four bases make up an alphabet of four letters, the genetic code.

And that is the key.

DNA is a code, a code that holds all the information

to make all living things.

An instruction manual to make a worm or a cat or a fly

or a human or a dinosaur.

Its regularity, stability, reliability and predictability,

even its relative boringness, make it the perfect system for storing

the vast amount of information necessary for building life.

Somehow, DNA must tell

each and every cell in the body what it is to become and when and where.

But how? 1950s scientists had a big job to do.

They had to crack the code.

So if you consider how a code works, let's think it out.

We've got four bases

and we know that we need to make 20 different amino acids.

So if we have a code that just consists of one base,

we could only make four possible amino acids, right?

Which isn't enough.

So if we had a code that consisted of two bases that could get

together in any combination,

how many different amino acids could we make then?

Yes? 16, exactly.

Not enough, is it? We need 20.

So if we had a code based on three bases that could get together

in any combination, how many amino acids could we produce then?

Nine? Not quite.

64! Exactly! More than nine and more than we need.

So, three bases would work.

And that's exactly what scientists found to be the case.

They worked out the code and they worked out that it was arranged in

threes - a triplet code,

with each group of three bases called a codon.

And each group of three bases, or codon, specifies - or codes -

for a particular amino acid. So we can see that here.

Here's a codon of three bases and that will give us

an amino acid, which we give another single letter code to.

We needn't worry about the amino acid codes for now.

So here's another codon - CCC - that gives us this amino acid, P.

And here's another codon - GAA - that gives us that amino acid E.

So we can start to decode this DNA sequence

and turn it into an amino acid sequence.

So we can see a growing amino acid chain in a protein.

I'm not going to waste my time decoding all of that now.

We've got one here that we prepared earlier. We know it's the same.

This is all these nucleotides, all these codons,

decoded into these amino acids. So here is our protein chain.

So a protein is like a sentence of amino acid letters.

And you can see that we've got punctuation in our sentences,

because it turns out that there are special codons that make

something like a full stop at the end of the protein.

Now, the question is, can we find some useful sentences in this

string of sequences that might represent useful proteins?

Can I have a volunteer to help me out here?

Let's have you on the end there. Thank you very much.

Let's have you on the end there. Thank you very much.

What's your name? Kirsty.

Right, Kirsty, if you'd like to come over here.

I want you to play a sort of wordsearch game, OK?

It's a very simple wordsearch,

nothing diagonally or backwards or any of those hard things.

It's just going to be a sentence going across like you would read a book.

Have a look at these letters

and see if you can pick out an actual sentence that might make sense.

Let's have a look...

What have we got?

"Make a..." "Make a liver...

"Make a liver cell." "Make a liver cell."

That sounds quite good, doesn't it? Have we got any more there?

Let's highlight that one, shall we?

"Make a liver cell." Have we got any more here?

"Make a heart cell." You're very quick at this!

Have you seen this before? No. Let's highlight that one.

So you've done something very clever here, you've found two genes.

So the first gene is making our protein called "make a liver cell"

and the second gene is making our protein called "make a heart cell".

What you think the "make a liver cell" protein

might be doing in the body?

Making a liver. Making a liver, absolutely.

And what do you think the "make a heart cell" protein might be doing?

Making a heart. That sounds pretty useful, doesn't it?

Kirsty, thank you so much for showing us the way.

So that's it.

Different proteins are made in different cells,

so that cells can look and behave differently from one another,

to make complicated things like worms and us, because of the DNA.

Hang on a minute...

If we go back to our worm, our worms been very busy

while we haven't been looking at.

Pete's been keeping score there and we've now have five cell divisions.

It's been very busy.

But we've seen that all these cells have come from this first cell.

So all these cells will contain exactly the same DNA

because DNA is duplicated each time a cell divides.

So now we've got ourselves a problem, haven't we?

All of our cells, no matter what their role is,

contain exactly the same DNA.

It's the same for any organism.

Each species is defined by its complete DNA system, it's genome.

So what on earth is going on? How does this work?

How do cells in us become different from one another?

And we've seen how different they can become.

And we've seen how different they can become.

But how do they do this if they contain the same DNA?

So, to find out,

scientists had to have another look at the code in even more depth.

And it turns out that there's more to genes than just

strings of codons. So let's have a look at our word search game again.

What did Sarah do to light up the sentence?

Let's go round the back here.

Sarah, what did you do to switch, to highlight these proteins?

I just pushed a switch.

So do it again. Off, on. Off...on.

You flicked a switch. Sarah flicked a switch.

And that's exactly what happens in a cell.

Genes can be switched on and off.

They can make a protein or not.

If they make a heart cell protein, it's going to be

switched on in our heart cells but off in our liver cells.

So we say the "make a heart cell" gene is EXPRESSED in our heart cells

and not expressed in our liver cells.

And that makes sense, because if your "make a heart cell" gene was expressed in your

liver cells and you made the "make a heart cell" protein in your liver cells,

your liver cells might start beating.

Do think that would be a good idea? No, neither do I.

So, understanding this problem of gene expression

is one of the key goals of molecular biology, even today.

So can we see this gene expression thing for real, in a real animal?

Oh, yes, we certainly can.

But curiously enough,

we need a little help from a glow-in-the-dark jellyfish.

And here's a picture of our jellyfish. Isn't it lovely?

This jellyfish is called Aequorea victoria

and it has a very special property, because when you shine blue light

on the jellyfish, like we are here, they glow green.

And they glow green because they produce a protein called GFP,

green fluorescent protein.

Not very imaginative, but it tells you what it does.

Green fluorescent protein.

So, the green fluorescent protein is produced by the GFP gene

when the gene is switched on.

And the glowing thing is really useful for scientists

because we can see it.

It's a biosensor.

But how does that help us understand the problem of gene expression?

Well...we can copy the GFP gene out of the jellyfish genome

and paste it into any gene in any cell in pretty much any organism.

The fluorescent protein will become incorporated into whatever protein

that gene normally produces, which will also glow.

So we know when a gene is switched on.

We know where it's switched on in what cells and at what time.

We know where it's switched on in what cells and at what time.

If the cell is green, then that means the gene is on.

I'm going to show you some very special worms again.

So here are some worms,

cruising around on their plate looking very normal.

But what Pete has done here, is to insert the GFP gene

into a gene that is only expressed - or switched on - in muscle cells.

It produces a kind of "make a muscle cell" protein, and that's

part of the reason why these worms wriggle like a worm should.

If we shine blue light on the worm,

which Peter is going to do now, then what we'll see are green spots.

Isn't that beautiful?

They are glow-in-the-dark worms.

The GFP, the green fluorescent protein, is showing us

the muscle cells of the worm and no others,

because this gene is switched on in muscle cells.

And we can see that the worms have two rows of these muscle cells

along each side of their bodies.

And they contract in a very co-ordinated way to help this

worm have this very elegant movement.

So it's the switching on of this gene in these cells,

and only these cells, during the development of the animal,

that makes the cells look and behave like muscle cells.

And this ultimately enables the animal to wriggle around.

So we've used GFP to track exactly when this gene is switched on.

Pete, thank you, your work here is done.

Ladies and gentlemen, Pete Appleford!

Ladies and gentlemen, Pete Appleford!

APPLAUSE

Next question. And I can see you're thinking this too.

How on earth do these switches work?

In the cell, what is the finger, the finger like Sarah's finger,

that presses the switch to turn the gene on?

Well, the answer is it's a protein.

A regulatory protein.

And I've got a model here to show you how this works.

If I can actually get it out of the box...

We've got a DNA molecule here.

This is the DNA and here is our regulatory protein.

And what that's going to do is bind to the DNA...

It sticks to it like glue.

It's binding to this DNA

and it's that act of binding to the DNA that is switching a gene on.

So, regulatory proteins are the things in cells

So, regulatory proteins are the things in cells

that switch genes on.

That's all well and good, isn't it?

But hang on a minute...

If this regulatory protein is the thing that is switching

this gene on, where did that regulatory protein come from?

Well, it's coded by the DNA, because all proteins are.

So it must be switched on by another regulatory protein.

So where does that regulatory protein come from?

So where does that regulatory protein come from?

Well, that regulatory protein must be coded for by DNA,

because all proteins are.

So that regulatory protein must be switched on by...

..another regulatory protein.

Complicated, isn't it? Where does it all start?

And that's what scientists are still grappling with today.

So, we've come a long way, but how on earth do we know all this?

So, we've come a long way, but how on earth do we know all this?

So, we've come a long way, but how on earth do we know all this?

How do we know which gene does which job? Which are the heart genes?

Which gene is the liver gene?

Which gene controls the very first cell division?

In fact, how does a cell know where its middle is anyway?

How do we work it all out? How do we work out which gene does which job?

Well, it may sound surprising, but what geneticists do

when they want to study a particular biological process,

is they look when it goes wrong because of a defect in a gene.

A mutation. OK, I've said mutation now. What do I mean?

A mutation is a change in a DNA sequence.

So the change in a DNA sequence can have big consequences.

Look at this one, for examples.

Look at this one, for examples.

This codon here, GAA,

has changed in this codon to GGA.

You're thinking that's not such a big deal, is it?

That's only one nucleotide in a string of DNA.

What's going to happen to the protein that this sequence produces?

Let's take a look.

This altered codon is going to give us the amino acid G.

And the amino acid G is going to go in place of the amino acid

that should have been produced here, called E.

So if we highlight our "make a heart cell" gene again, what happens?

There's a mistake. What does it say now?

Make a what? Make a hgart cell.

Does that sound like it's going to do the job?

ALL: No. It doesn't.

That does not sound like it's going to do the job and make the heart.

So you can now see the consequence of a mutation in a DNA sequence.

In this case, we are going to end up with heart cells that don't

actually do their job, so that would be our mutant animal.

Our mutant animal would have a dodgy heart.

Right, shall we meet some real live mutants now?

So, time to meet another one of our hero model organisms.

Now, it's not worms this time, it's something else.

Does anyone know what is in this box of rotten bananas? Yes?

Maggots?

Well, probably a few but there's other things in there as well.

Yes? Flies. Flies. They're very nice, aren't they?

This is the fruit fly, Drosophila melanogaster.

Another one of our hero model organisms that has

so much to teach us about biology,

and in particular developmental biology.

Some of the flies in this box actually have a few issues.

We've got some mutant flies in this box.

But they're very small, so we need to look at them

under a microscope to see what they really would look like.

So our first picture is going to be a normal fly.

This is the head of a fly.

You can see its very beautiful eyes, made of all these ommatidia

on each side of the head.

And then we've got the antennae sticking out as they normally would.

So everything is present and correct in this fly. It's a happy fly.

It's flying around in our box of bananas very happily.

But the next fly has something wrong with it.

The normal one is on the left and the mutant on the right.

Can anyone spot the difference?

Yes, what do you think, Ollie?

It has legs growing out of its face.

It's got legs growing out of its face.

I wouldn't like it if that happened to me!

So, this is something very wrong.

It's got legs instead of antennae.

I think that is a big thing to get wrong.

And this problem is caused by a single mutation in a single gene.

So when this protein doesn't work properly, the wrong switches

are flicked and hey presto, you've got legs sprouting from your head.

Nasty.

Now, the really important point here, though,

is that these mutant flies reveal what we call a "how do we know this?" moment.

We know that this gene,

the gene that's gone wrong in these mutants, must be absolutely

crucial for putting antennae in the right place, and not legs.

And when it goes wrong, you can see what happens.

So we start with the mutant. That's the approach.

And then we work out which gene has gone wrong and that tells us

which gene normally makes this process go right.

So, mutants are extremely useful. They reveal how processes work.

And in the lab, we use special chemicals that increase

the chances of mutations occurring in the DNA of the organism

and then we look through loads of mutants until we find a fascinating

one, like a fly with legs instead of antennae, and we use that

as a way of finding what the gene is that normally makes that go right.

So this is the genetic approach.

Studying mutants opens a dialogue with the organism about what genes

are the most important for a particular process.

We can ask pretty much any question about biology in this way.

It's incredibly powerful.

Some people call it the "awesome power of genetics".

And now I'm going to introduce you to someone who

is particularly good at it.

Goodness me! Good heavens! It's Paul Nurse! Hello, Alison. Welcome!

Lovely to see you.

What's the deal with the bike? It's a terrible bike. It is.

There should be handlebars there but there's pedals.

Something wrong with the instructions.

It's just like the fly you're all looking at. Yeah.

Pedals instead of handlebars. There's something else wrong with this bike.

What else? It's dangerous - it's got no bell. No bell?

But I understand you got a Nobel Prize.

LAUGHTER

That was a very bad joke, Alison. I know, I couldn't resist.

Perhaps you'd like to stay to tell us

something about how you got your Nobel Prize.

I was interested in yeast, and in my pocket I have some growing yeast.

How many of them are there on the plate.

Each of these pink blobs

has got about 10 million to 100 million cells.

So they're really small. Very, very small.

Ten micrometres, much smaller than flies. Much smaller than worms.

Let's have a look at them under the microscope.

I think you have some under there, don't you? I hope so. Oh, look!

That's what I devoted 40 years of my life looking at.

LAUGHTER

And are they dividing? These are fission yeast.

They're like little sausages and they grow longer and longer,

and when they get to a certain length, they divide into two

and then into four, and then into eight, just as we saw earlier.

And you spent 40 years studying that process.

I'm a very sad person, Alison.

So, how did you do it?

Well, me and my colleagues,

including yourself at the time, we looked for mutants,

and we looked for mutants that were defective in genes that were

important for cell division.

Now, imagine what would happen if you could grow but you couldn't divide.

What would happen is that those sausages would get longer

and longer and longer.

And so if you look down the microscope, that's what you'd see.

So this is a cell division control mutant.

This is a cell that contains a gene that is defective in completing

the cell cycle. It can't do it. There must be lots of these genes.

the cell cycle. It can't do it. There must be lots of these genes.

We now know - we didn't at the time - there's about 300 genes in this

yeast that are important for controlling its division. Wow. Lots of genes.

But amongst them there's one or two that are much more important.

These are the ones that tell the cell whether to divide or not.

And these are the ones that tell the cell how fast they should divide.

It's rather like the accelerator in a car.

There's many bits to a car,

but if you want to control how fast it goes you work on the accelerator.

So that tells us an awful lot about the yeast and,

no disrespect, you know an awful lot about yeast.

What does that tell us about other organisms?

You're right, I am very interested in yeast,

but I don't think the rest of the world is. I think these guys are.

But we are very interested in ourselves. Oh, yes.

So the question is, do the genes that control the division of this yeast

also control the division of all the cells in us?

How do you find out?

Well, you can look to see

if there is a gene the same as the gene here in humans.

How do you do that?

Well, it's difficult, because the last common ancestor

between yeast and ourselves was probably 1.5 billion years ago.

So we are nothing like yeast. Nothing like yeast.

And to put that in context, dinosaurs went extinct 65 million years ago.

That's just a flash in time. It's 20 times older.

So this is a difficult project. So what did we do? What we did,

and it was done by somebody in my lab called Melanie Lee,

and she took human DNA, chopped it up into pieces

and then sprinkled it on to the defective yeast cells.

And the idea was that

if there was a human gene that did the same job as the gene

that's defective here, if the yeast took it up,

then it could substitute the defective yeast gene.

So it would rescue those mutants? It would rescue that defect.

And the genes were almost exactly the same.

Despite the 1.5 billion years, they were almost exactly the same.

So when we find that out, then we can start to think about

how this might help us in medicine, right?

We do, because what it tells us is the way in which yeast cells

control their division is actually exactly the same way

as how we control our cell division.

Which can sometimes go wrong.

Which can go wrong, and when it goes wrong we get disease.

The most common one that goes wrong is cancer.

And what causes it is activation eventually of these genes

that cause cell division.

So working on yeast can even help us in cancer research.

It can. If we want to think about new ways of treating cancer, new therapies,

we have to understand what's going on during the cell division process

and we can work it out much more quickly working on yeast

than we can on human cells. Paul, that's amazing.

Ladies and gentlemen, Nobel Prize winner Paul Nurse.

Thank you!

So...this has been quite a journey, hasn't it?

Isn't it extraordinary how organisms develop from a single cell?

How those cells know what to do and how it's all written in the genes.

Next time we'll see how the developmental programmes

we discovered today can vary over time, and understand how this is at

the very heart of evolution and the diversity of our fantastic planet.

Thank you and good night.