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How chromosomes split in cell division -

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Robyn Williams: How does the cell with its double set of chromosomes pull apart into two complete
daughter cells? How does the cell sort two gigantic sets of computer code exactly every time?
That's the riddle. Kim Nasmyth likened it to socks.

Kim Nasmyth: To give you an idea of how this relates without thinking about molecules, I could tell
you a little riddle. And the riddle is the following. There are two blind men who go shopping, and
what is the one thing that you most often have to go and buy when you go shopping when you're a
man? It's usually socks because you put them into the wash and one of them disappears. And even
though they are both blind it turns out that their wives like them to wear coloured socks and their
wives like variety. So each of them goes off and buys five pairs of socks; a blue pair, a red pair,
a pink pair, a green pair, a orange pair, say. Now, the shop assistant finds this a somewhat
eccentric purchase and gets slightly muddled and puts all ten pairs of socks into the same bag and
they leave the shop, and one of them has got a bag with ten pairs of socks, the other has no socks.

Shortly before going their separate ways and going home and showing their socks proudly to their
wives and saying, 'Look what we've bought today,' they realise that one of them has got all the
socks. They say, my God, how can we sort out this problem so that each of us has one blue pair, one
green pair and one orange pair et cetera? The question, the riddle, is the following: how do the
two blind men achieve this goal without their wives helping them, without the socks being different
lengths, without the socks having any different texture or whatever? As far as the blind men are
concerned they wouldn't be able to tell the blue pair from the red pair. But how would they ensure
that they could divide the socks up so that each of them would have two blue socks, two red socks
et cetera?

So that's the riddle, so I ask you Robyn; how would you solve this problem? It's a very simple
solution.

Robyn Williams: A very simple solution?

Kim Nasmyth: A very simple solution.

Robyn Williams: Well, I'll defer to the professor from Oxford; you tell me.

Kim Nasmyth: You have to do better than that!

Robyn Williams: I have jetlag, I've only just landed here!

Kim Nasmyth: I'll give you a clue. What is different from a pair of socks that you've just bought
from a pair of socks that you might, if you're lucky, retrieve from the wash? What is different?
When you buy socks from a shop, you always buy them as a pair...

Robyn Williams: Yes, they've got this little hook at the top which keeps them together.

Kim Nasmyth: Exactly, so the two socks are held together. So because they're held together, what
the blind men can do is they can take out one at a time and they can take the two socks, and even
though they are blind, but because they are held together they can pull the two socks in opposite
directions, then they take out a pair of scissors and cut that little hook, and then they will take
those two blue socks and put them in separate piles, and then they do that ten times and each of
them will end up with two blue socks, two red socks, two green socks, two orange socks, two yellow
socks, et cetera.

Robyn Williams: A complete set, yes, right.

Kim Nasmyth: Each one ends up with a complete set.

Robyn Williams: Of course it depends on there being pairs hooked together, and you're implying that
the DNA is in the same sort of position.

Kim Nasmyth: Yes. So this problem that the blind men have is essentially the same problem that each
one of our cells has. It's not five pairs, it's 46 pairs. What happens is that after the
chromosomes are copied (and we could translate 'chromosome' for 'sock') you now have the two sister
chromosomes not just floating around in the cell, they're held together by little hooks, which
means that if the cell starts to try and pull them in opposite directions it will generate tension.
And if the cell can measure that tension and say, okay, I can measure that tension then I know I'm
puling them in opposite directions. But if the cell instead pulled them in the same direction it
wouldn't generate the tension. In fact what happens is that cells create fibres, they're called
microtubules that can grow and shrink, and when they grow they can sometimes clamp onto
chromosomes, and when they shrink they'll pull the chromosome back towards them. So you end up with
a sort of tug-of-war; the fibres trying to pull the sister chromosomes in opposite directions but
the little hooks holding the chromosomes together, resisting them. That is the climax of the whole
cell division process, is to create this state of tension.

Robyn Williams: How did you find this out? Was it by doing experiments?

Kim Nasmyth: No, what I should make very clear is that the person who first had this idea about
tension and the stabilising the fibres and attach the chromosomes...a man called Bruce Nicklas who
was a very talented cell biologist who worked with grasshopper chromosomes. But what we have done
in the last ten years has been to discover the little hooks that hold the two sister chromosomes
together, and then we've discovered the enzyme which, when all of the 46 pairs of chromosomes come
under tension, then and only then this enzyme is activated and it destroys the little hooks. What
that then does is because they're being pulled in opposite directions, the chromosomes then are
pulled to the opposite sides of the cell.

So what we've discovered is that when the DNA of a chromosome is copied, the two sister DNAs are
not just floating around in the cell, they're held together by, in fact, not a hook, a ring...it's
a very beautiful ring, it's a huge ring, and it seems that it can open and shut. When I was younger
I used to spend a lot of time climbing. One of the key pieces of equipment if you're a climber is a
rope, and another key piece of equipment is a so-called karabiner, a little ring which you can
attach to the rock and then clip the rope into the ring and that helps you falling down the
mountain. Well, essentially the cells make a sort of karabiner which is a ring that can be opened
and shut.

What we think is going on is that after the double helix is copied and you end up with two sister
double helixes, those somehow enter the same ring and they're held together by this ring. That is
what holds the sister chromosomes together and that is the mechanism by which the chromosomes
resist the microtubules from pulling them apart and generates the tensions that ensure that they
will be pulled in opposite directions. And then when everybody comes under tension, all 46
chromosomes have reached this state of the tug-of-war, then what the cell does is it makes an
enzyme which cuts the ring open. It literally breaks open the ring and now the two DNAs are free to
be pulled in opposite directions. And that, in very, very simple terms, is what we've discovered.
And when you see these wonderful pictures of chromosomes moving just before division, when the two
sister chromosomes associated and then suddenly they split and go to opposite...what's happening
there is the ring is being broken open by this enzyme.

Robyn Williams: Apart from the beauty of that discovery, what do you think it will be used for?

Kim Nasmyth: It is conceivable that drugs against the enzyme that breaks open the ring could
eventually be targets for chemotherapies against cancers. I don't think we really know whether they
would be good targets but it's not inconceivable in the future. Every time a tumour cell divides,
these rings are active and the enzyme that breaks them open is active, and tumour cells do too much
of this and so conceivably could be targets for chemotherapy.