Cell City – Transcript: Programme 3
Keith Roberts:
The country’s fuel crisis took a turn for the worse today. Half of Britain’s thirteen
thousand petrol stations have now run dry. In parliament, the Prime Minister said
local authorities are to be given special powers to ensure that precious fuel stocks
are to go to where they are most needed. And he urged everyone to act responsibly,
at a time of national crisis.
Cities have to constantly monitor their health, their economic status, and their
environment. And they need to communicate this information to neighbouring towns
and cities throughout the country. They do this through a variety of means, through
email, phone, radio, newspapers, word of mouth and television.
Now a cell in our body, in a state of distress, and lacking nutrients, is in exactly the
same position. It too needs to communicate this information to it’s neighbours, just
as cities won't survive without a constant exchange of information and materials and
resources between cities, cells too, require a constant input of information.
Cells monitor their environment. They need to know how much energy they have.
How big they are, have they got appropriate nutrients, appropriate growth factors?
Who are their neighbours? Where are they? A cell that deprived of this signalling
information will die.
Keith:
Signalling sustains all life and is crucial to our own creation.
That one sperm cell from the countless energetic candidates swimming towards an
egg cell actually completes such a perilous journey is, in itself, quite something.
But all this effort would be as nothing without a signalling wave within the egg cell that
welcomes the sperm.
This prevents other sperm entering the egg, allows fertilisation and the development
of a human embryo…
Martin Raff, University College London:
The goal in developmental biology is to understand how a fertilised egg develops into
a complex structure such as a human being. Where a single cell, a fertilised egg,
that has to divide and divide and divide, to the, billions of cells that make up our body.
While they are dividing and dividing and dividing, they are also becoming different
from one another, specialising. A process called differentiation, and so, you end up
with many hundreds of different cell types.
Keith:
Each cell type has a dedicated function – such as cells in the blood… in the brain, in
the heart muscle.
It’s these specialisations that are the key to why animals and plants are so
successful.
Martin Raff:
How do these cells become organised, so that you look like a human being, with hair
and limbs, and liver and lungs and so on. Just as people in a society have to coordinate their efforts, cells have to obey the signals they get from other cells in the
body, so that the organisms can work as a co-ordinated assembly.
You can't have everybody driving their cars and not obeying stop signs, and stop
lights and so on. It would be chaos. We know that cell growth, like cell division, cell
survival, cell movement, depends on signals from other cells. If there is no signal,
cells don’t grow, they don’t divide, they don’t move, they need signals from other cells
to do this.
The thing that we are learning a great deal about is the nature of the signal, and it
turns out that there are relatively few signals, maybe a few hundred, rather than
thousands, which is, a little bit surprising. The same signals are used over and over
again, in different circumstances.
We are learning a great deal about the receptor mechanisms that the receiving cell
uses to recognise the signal, and transduce it into an inter-cellular signal. It changes
the behaviour of the cells.
The way the cells develop, the division, where they end up, how they stick together,
depends on molecules. Proteins, mainly. And signals between cells, so that cells
know where they are in relationship to their neighbours, and because of signals and
gradients of such signals - how they are recognised, how cells respond to them. You
know, whether the proteins that stick cells together in a particular combination.
At every level, we are beginning to understand how a fertilised egg develops into an
animal or a plant.
Keith:
Cell signalling is vital to the healthy function of our bodies. When it goes wrong, such
as with uncontrolled adult-onset diabetes, also known as type 2 diabetes, there are
clear health risks.
Jeremy Tavare, University of Bristol:
The consequences of having type 2 diabetes are very severe, like blindness and
heart disease. You often might have, might actually get type 2 diabetes in your
twenties or thirties, but it is not diagnosed until you are fifty. Twenty years later. So,
you’re sitting there with the disease for a very long period of time. And that, that’s why
the complications can be quite severe, because it often is not picked up until you
have the complications, so that is why it is very important to be able to understand
how insulin works. And at the molecular level, at the cellular level.”
So we’re adding insulin and the protein is starting off in the cytoplasm isn’t it? And
moving into the plasma membrane.
Keith:
Cells need glucose to make energy but that process cannot even begin without a
signal from a protein called insulin.
Jeremy Tavare:
And what’s going wrong in type 2 diabetes, is that signal is not getting through
properly. The insulin arrives, often in very large amounts, but it can't produce a
signal, inside the cells.
If we think about how insulin works when it arrives at a cell, it, that to me is a bit like a
ship, coming into a port. And the ship has a number of containers on board. And I
consider the containers to be the signal. So, the ship can't get into the city centre. It
is like insulin doesn’t know how to get into the cell. But you’ve got to tell the city
centre that the ship has arrived.
So, I think the insulin coming along, with its containers, and the containers are the
signal. The signal, the containers are transferred onto lorries. These lorries then
take the containers, the insulin signal, along roads, along motorways, down into the
city centre. And that then informs the city centre that the insulin as arrived, and that
the city centre has got to respond appropriately.
So, in terms of type 2 diabetes, where you don’t respond to the insulin properly or
your muscle cells, or your fat cells and your liver cells don’t respond properly.
Now, lets think about that in terms of the lorries, that are taking the containers down
to the city centre. The containers are the signal, the lorry suddenly comes across
some road works, and it can't get through properly. And it can't get through fast
enough, or it can't get through at all. And that is a very nice analogy with what is
going on in type 2 diabetes, where you can't respond to the insulin. Because the
signal can't get through.
Drugs now are being developed that, that directly treat that, that help the signal get
through to the right place, get in, they help to repair the road. They help getting the
road back into, to operational shape, such that the traffic will flow properly.
Keith:
Cell research is also helping to develop medical treatments of a very different kind.
Fiona Watt, Cancer Research UK:
For the treatment of people who have been badly burnt, the normal skin will come
from a tiny piece of the person’s own skin that hasn’t been damaged.
Keith:
For over twenty years, Fiona Watt’s lab has been pioneering work with adult stem
cells – and they are now able to use these extraordinarily useful cells to kick-start and
successfully grow healthy human skin.
Fiona Watt:
When we want to grow human epidermis in culture, we take a tiny piece of normal
undamaged skin, separate it into it’s component cells, and then put those cells into
what we call a tissue culture glass.
Now, you might be sceptical about whether there is actually anything in this glass, but
when we look under the microscope you will be able to see many, many millions of
cells, all tightly packed, and making the artificial epidermis.
Keith:
It is clusters of adult stem cells – seen here in green – which have the capacity to
both continuously divide and differentiate. It’s these cells that allow the production of
human tissue, in this case skin.
Fiona Watt:
You start to see a delicate wavy sheet of cells. If we leave that a bit longer, then the
whole thing will detach it, and we have a beautiful piece of artificial epidermis.
One percent or less, in the dish, are stem cells, but, if they hadn’t been in the dish to
start with, you wouldn’t have had a cultured epidermis. You wouldn’t have been able
to generate it.
Martin Raff:
There’s another kind of stem cell called the embryonic stem cell. It comes from a
very early embryo that is capable of dividing indefinitely in a culture dish. And at the
same time, giving off all the different cell types in an animal. Everything. The nerve
cells, the muscle cells, the blood cells, everything.
So, needless to say, people consider that to be, very promising for cell therapy,
because one cell, can be divided up and give rise to anything.
If you could control
it, to divide, and give rise to muscle, you could use it to repair muscle, and give rise to
nerve cells, to repair brain, and so on.
That is why there is so much enthusiasm about the embryonic stem cells. The
problem with the embryonic stem cells at the moment, is an ethical problem, because
to get those cells, you have to get them from an embryo. A very early embryo, and
there are some people who consider the early embryo a human being. And there are
others who say this is much too early to be a human being.
I mean, it has a potential to become a human being, just like other cells in the body
have the potential, but that it is not a human being yet. So, that is why there is an
ethical problem.
Fiona Watt:
The scientists who actually do this research are not interested in procuring babies for
ulterior motive. They are not interested in cloning themselves. What motivates them
is their desire to improve human health. Plus, genuine curiosity about finding out
about basic mechanisms that control the way cells behave.
You could take about a square centimetre, of human skin, and within about three
weeks or months, you’d have enough to completely cover the donor. I know for
example of a case, of someone whose life was saved. And the only piece of
undamaged skin that could be used for a biopsy came from the sole of the foot. So,
this person has been completely covered now, with cells derived from a tiny piece of
his own skin.
Keith:
At the same time, all of us actually shed skin everyday.
Cells below the surface are constantly dividing, producing cells that develop into
mature skin cells that in turn die and eventually fall off.
The dead skin cells are akin to leaves shed from a tree. This shows how cell death is
intimately involved with the processes of life.
Martin Raff:
The only reason any cell in your body is alive is because other cells are constantly
signalling it. Don’t kill yourself. Just like an animal or a plant can die in many ways.
But there is one way which is most interesting.
There is an active programme operating within the cell, to kill it quickly and neatly. In
a way that a neighbour will eat it, almost immediately.
Every cell in your body has that programme built in, and ready to go. The
programme doesn’t run, because the cells are signalled by other cells, to keep this
death programme off.
Robert Horvitz, Massachusetts Institute of Technology:
Think about construction, on one striking example of programmed cell death involves
the centrally, the sculpting of an animal. And there are some classic examples of
this.
Take a frog. A frog develops as a tadpole. And what happens to the frog is that the
tadpole loses it’s tail. You don’t see a tail on a frog, but the tadpole has a tail, and the
tail regresses. And it regresses by this natural process of programmed cell death.
When you build the city, and when you build a building, one at a time, you always see
it surrounded by scaffolding. The scaffolding is used to help put up the main
structure, and then at the end of the process the scaffolding is removed.
We too, are built with scaffolding. A simple example, look at our fingers, or our toes.
And you see here separate digits, and between the digits is nothing. But, that wasn’t
always so. In-utero, there are so called inter-digital regions of webbing.
And what happens is that the fingers and toes grow out, with this webbing, and then
after they are grown, the inter- digital webbing goes away. And it goes away by this
process of programmed cell death.
In a developing mammalian brain, as many as 85 percent of the developing nerve
cells, in certain places in the brain, at certain times, die. By programmed cell death.
In our immune systems as adults, as many as 95 percent of certain classes of
protective blood cells in our bodies, die, by programmed cell death. Programmed cell
death is pervasive. In the animal kingdom and in us.
We have not been designed de-novo. Say, with some very carefully defined
algorithm saying this is how we are going to make a person, or a duck, or a moose,
or whatever it happens to be.
Rather we have evolved, and the process of evolution is a process of modification.
When you look at the evolution of the city, as opposed to the evolution of the
organism, again, most cities are not designed by some architect, or city planner.
Rather, cities are grown up over time, and they became, they began initially very
small, very simple. Things became added. There was an expansion of, some of the
older things were then taken down. Sometimes left open, sometimes new things put
in their place.
And we evolve in the same way as a city evolves. By a process of growth and
division, and modification, and deletion. And the deletions that occur in, in the
evolution of an organism, are deletions that are effected by programmed cell death.
Martin Raff:
And in a way, it is simply an example of the social controls where cells talk to one
another to control the behaviour, all of the behaviour of every cell in the body, so that
it works as a co-ordinated community.
Robert Horvitz:
And it can go wrong. There can be, too much cell death, there could be too little cell
death.
If there is too much cell death, cells that should live instead die, and we know of
many diseases, many disorders in which there is too much cell death. The Neurodegenerative disorders provide examples of this. Alzheimer’s disease, Huntington’s
disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis are all nerve
degenerative diseases –diseases in which nerve cells, particular classes of nerve
cells die.
If there is too little cell death, what happens, you have cells that should die, instead,
living. And a striking example of that is cancer. Most people think about cancer as
being to much cell division, and indeed many cancers are caused by too much cell
division.
If you have too much cell division, cell number goes up. If you have too little cell
deaths, cell numbers go up. Certain cancers are just like that, too little cell death,
follicular lymphoma is a prime example, too little cell death leads to cancer.”
Keith:
Father and son, Martin and Jordan Raff, are both established cell biologists.
The question that intrigues them both is why do we inevitably change in appearance,
as we grow older? And can science do anything to stop the ravages of time?
Jordan Raff, Cambridge & Martin Raff:
J: You look a lot older than I do.
M: And do you know why that is?
J: No
M: Because I’m older than you are.
J: Is there anything I can do to stop this happening?
Tom Kirkwood, University of Newcastle upon Tyne:
What we believe drives the ageing process is that, as we live our lives, our cells
accumulate a huge variety of faults. Simple things, individually each fault is a tiny,
maybe even trivial insult to the normal working cell.
But as we get older, the burden of cells with faults increases, and the fraction of cells
within body that are compromised by this accumulation of faults, also increases, so,
eventually we see, in later years, that things just don’t work as well.
Martin & Jordan Raff:
M: Cells need energy to do what they do, and move around and so on.
J: Right.
M: And the way they get that energy is chemically converting carbon compounds into
energy. And they use oxygen to do that. And there is a cost to that, and that is
oxidation of things like proteins.
Tim Kirkwood:
Oxygen is an essential chemical, but it’s also highly toxic. And if the oxygen breathes
in and finds its way to our cells to fuel the reactions that sustain life, a small
percentage of those molecules can slip away and become free radicals. These are
almost like, molecular sparks within the cell. That can strike any part of the cell, the
DNA, a membrane, or protein, whatever, and damage it.
Jordan Raff:
Right, so all it is, is that, as we live, our proteins are getting oxidised, the cells are
basically just getting damaged, and that is why, skin starts to look a bit saggy, and
you get wrinkles, and that’s why I'm going to start looking like you in a few years.
Martin Raff:
The bad news son, that’s it.
Jordan Raff:
Now, if the protein clearance systems are not perfect, then you accumulate bad
proteins within the cells. It’s like a sort of molecular sludge, really.
Tom Kirkwood:
And the analogy here is with a city that has an ageing sewage system. I mean, we
know an old city has a sewage infrastructure that was built in the Victorian era. And
we’ve fiddled about with it, and tried to maintain it since then. But, we haven't
radically gone back and re-engineered the sewage system. So, we see, live with the
consequences in cities, of the decay and collapse of this infrastructure. So, a similar
sort of process explains what we see in ageing brain cells, where there is an
accumulation of fairly non specific proteins that just simply gradually builds up, and
fills up parts of the cell.
Martin & Jordan Raff:
J: Surely there is something I can do, to stop me looking like you?
M: There is nothing out now that actually stops the ageing process. You can make
your skin look a little better, and I advise you to do so.
J: Now, you don’t see me uptight on that. I tell you sire,
M: No, but I don’t think any of those things actually, in the long term, stop the ageing
process.
Tom Kirkwood:
The process of accumulation of wear and tear, damage to the structures, in both the
city and the cell are very similar. Now, cells can keep going indefinitely. Just as
cities can keep going indefinitely. And the way they do that is by investing in
maintenance and repair programmes.
Martin & Jordan Raff:
J: We’re always told that we should keep exercising, to try and keep fit, but surely the
exercise would generate a lot more oxygen radicals, and a lot more damage. So, the
best thing would be to not do any exercise at all?
M: Well, in the extreme form that is right. That is absolutely right. And as you know,
if you cut the wings off a fly, it will live longer, because less energy expense, less
oxidation, is the simplest definition.
And every organism, if it has ever been tested, if you restrict the amount of food they
eat, you don’t starve them because then they’ll die, but if you just restrict it by 20 or
30 percent, that expands the lifespan, in every organism that has ever been tested.
The simplest view, they are using less energy, less oxygen damage, and therefore
they live longer.
J: So, would you advise us not to take any exercise?
M: No. Because exercise does different things. It not only increases our rate of
damage, but it protects your heart, for example. It decreases,
J: So, limited exercise is okay, but don’t go overboard on it, right?
M: If you get the feeling, one exercise and lie down, until it goes way. That’s my
advice.
J: I know that is your advice, and you’ve put it into practise over many years.
Tom Kirkwood:
But you don’t want to squander impossible amounts of resource on maintaining your
cells well enough that it can last indefinitely, if the reality is that you don’t need it to.
So, it all comes down to budgets. And we know in cities that what determines the
longevity of the city, is the well being of its infrastructure, is exactly that. How much
tax are you prepared to pay? Just the same in the cell, how much tax is the cell
prepared to pay, to keep itself going?
Martin & Jordan Raff:
J: I'm glad we’ve had this little chat, it’s really been very informative. So, where, is
there anything else, I was just wondering if there is, over the years, really you should
have told me all about sex, and life… Why didn’t you do this when I was a bit
younger, when I was a little kid?
M: We talked about nothing but sex from the age of three weeks, on. That is all we
talked about and look at you. It didn’t work.
J: I never let on. (ha ha).
M: I mean, you have children don’t you?
J: Yeah, yeah. How does that happen?
M: I have no idea.
(Laughter)
Keith:
Joking about the birds and the bees, that’s fine! But looking to the future, as we’ve
heard from many scientists throughout these programmes there’s a great deal more
to discover.
Tom Kirkwood:
I think the future is very exciting because if we can find ways of reducing the
exposure of cells to the stresses that damage them. Or boosting, enhancing the
natural maintenance and repair systems that keep us well as long as they do already,
then we may be able to keep ourselves in good shape for longer. It gives us a better
chance of reaching old age, in good health, and giving better quality of life.
Paul Nurse:
Unless we understand how cells work, we’ll never understand why they go wrong.
And that means we’ll never properly understand disease. So, we now have the
opportunity to really understand how cells work, and it gets us, also, nicely into the
secret of life as well. So that is a great thing. But, additionally to that, understanding
basic cell processes will really help us tackle important human diseases.
Martin Raff:
The details of how the brain works, how we think, how we talk, is really the next
frontier. If I were young again, that is what I would do, I would do molecular cell
biology of behaviour and higher brain function. Because we know so little, it’s all to
be learned.
Lee Hartwell:
If we really appreciated how complex it was, we’d probably give up. But we are
basically optimists.
Tim Hunt:
It is good to be clever, but you can be much too clever. Nature is always more
complicated, more interesting, more fascinating, than you could ever possibly
imagine. You’ve got to get in there, get your hands dirty, and find out.
Julie Theriot:
The next 20, 30 years of biology are going to be as exciting as biology has ever done,
as a science. More probably like the golden era that the pioneer physics was back in
the 50s when we’d just learned how to smash atoms. It is a revolution.
Keith:
We’ve found it helpful to look at cities in order to better understand about the function
of cells. But, I’d like to turn that metaphor on it’s head, and ask, are there things that
we can learn about cities, by looking at cells.
The politics of cells, are very robust, after all they’ve survived the tough selection
pressures of billions of years of biological evolution. Cells are highly organised, and
very efficient. They are neither too big, nor too small. And they’ve got effective
communication systems with which to communicate with their neighbours.
They’re also very co-operative. All of the parts of a cell work together for the greater
good of the whole. A sort of cellular version of mutual aid.
So, next time we walk around our cities, perhaps we’ll view them just slightly
differently and perhaps we’ll also be better equipped to think about ways in which our
towns, villages, and cities might be better managed to survive the tough selection
pressures that they’re going to face, undoubtedly, in the future.