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Vitamin C synthesis -

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Robyn Williams:Let me ask you a question; why a couple of billion years ago did nature invent
vitamin C, and what was the point? You'd think we'd know all about that, but not so.

Steven Clarke: You know, when we looked at the initial results that we had, we weren't sure. Once
though that we were able to look and see what the possibilities were, and we said, 'Can we be lucky
enough that we've got the last piece of the puzzle?' And we did the experiments and it was there.

Robyn Williams: Steven Clarke is a professor of chemistry at the University of California Los
Angeles, and he was convinced that vitamin C was an old story, until they looked into it. Why was
it made in plants, and how? Why so important for humans? How could the story still be incomplete?

Steven Clarke: The puzzle for us was a puzzle of aging, but the puzzle that we actually solved was
a slightly different puzzle of vitamin C synthesis. One of the things that when you look at in
science you're never quite sure where you're going; we were going in one direction, we took a bit
of a detour and we came up with something that was different and to us (and I think to others) very
exciting. If you had asked me about vitamin C biosynthesis in plants I would say that was probably
solved by 1910. It's in the text book. If a student came to me I'd say, 'Go look in the textbook,
it's done.' And to find out that it wasn't done, that we didn't know this crucial biochemistry, was
a surprise, and that we contributed to it, it just made my year.

Robyn Williams: Let's look at why vitamin C is there in the first place, going back vastly in
history when there wasn't much oxygen in the atmosphere, when oxygen was produced as a kind of
by-product. Did vitamin C play a part really in helping organisms resist what seemed to be a poison
after all?

Steven Clarke: We don't know what was happening two billion years ago, but we can make a pretty
good guess that was involved because the problem was plants figured out a new way to make energy
and make a lot of it and make it quickly, and the ones that could do that were at a tremendous
advantage, but with one problem; they made one of the most toxic molecules involved in nature and
that's oxygen. There was very little or no oxygen in the environment at that time and these plants
started making it. The ones that weren't prepared, died.

But then there was some mutations, some evolution of defence mechanisms, and plants began to be
very good at actually resisting the oxygen, and so they could deal with this toxin. What are the
molecules? We're still learning what they are. When your mum says, 'If you want to be healthy, eat
your fruits and vegetables,' a large part of that may be taking anti-oxidants, and different ones
have been teased out, but certainly vitamin C stands at the top of the heap of these collections of
molecules. Plants figured it out, they saved themselves.

Animals then learned how to use the oxygen, so we can't live without it, and we learned to use the
oxygen basically to make energy and to succeed much better, but to do that we had to take some
things from plants. One of the things that we presumably took was vitamin C but we made a different
way, and presumably if we can eat enough plants we can take enough of their other protections, some
of which we know about, some of which we don't know about.

Robyn Williams: So, by definition, a vitamin, even though we might get plenty of them from bacteria
in our guts without knowing it, I think the definition is it's essentially something that comes
from outside that you need to keep alive. This question of synthesising it in the that
you seem to have got the mechanism, what does that mean?

Steven Clarke: I think the most exciting parts of it now is that some plants may survive better
under oxidising conditions than others and we have a possibility now of perhaps engineering plants
(this hasn't been done yet) to actually make them make a better vitamin C synthesis for themselves
and make them more resistant. As our environment gets more toxic and you live in Los Angeles you're
breathing oxygen and oxidants, you're not doing so well. And if an organism can protect itself
better, so much the better. So we may make better crops. This is not in our expertise but this is
what we throw back at the field, we say, okay, we're lowly biochemists here, here is something
exciting that you might be able to take a run at.

Robyn Williams: And the mechanism is fairly straightforward to describe? They could actually
emulate it by using genes?

Steven Clarke: Yes. In theory, yes. In practice, things are often much more difficult. You can say
this is a rate-limiting enzyme, if we can now have a gene and over-express it, that will work.
That's the idea, and people have actually started doing that and seeing some over-expression. How
much over-expression do we need? Can we make it in specific tissues? Can we do it in the right
place so actually plants live better? That, we don't know yet. But that is the hope, that you're
going to make plants that survive better themselves, and perhaps plants that are more nutritious.

Robyn Williams: Many years ago, actually in this parish in Los Angeles, I used to interview Linus
Pauling who used to visit Australia, often talking about the Bomb, but sometimes he was talking
about vitamin C, as well as covalent bonds, one of the greatest chemists in the history of the
known universe. But he was always advocating the fact that you should take a great deal of vitamin
C and many of the studies over the years have shown that apparently this is not the case, that if
you eat too much, you pee it straight out. What's your view?

Steven Clarke: Certainly if you eat too much you pee it straight out and you can damage the kidney.
They've changed the recommended daily dose but it was very small previously, basically to avoid
scurvy. So some of the people were saying you take ten grams a day, at that point you may be
hurting your kidneys, but one or two grams a day may be actually very good, and it may be different
from people. You and I have 999 of our DNA bases the same, the 1,000th one is different, and those
differences in us may make huge differences in how we respond. It may turn out that some people
respond much better to larger doses of vitamin C than others and it's one of the problems now in
testing new pharmaceuticals because if there are going to be differences, how do you handle that?
And if there are subgroups that may respond better, how do you tease that out?

Robyn Williams: There are two aspects here; one of them is antioxidant and the question of aging,
and the other one is cold protection. Why would vitamin C give you protection against a germ like a
cold virus?

Steven Clarke: We don't know and I certainly don't know, and I don't think my colleagues know, but
it may be it has a completely different function. There is an antioxidant function of vitamin C,
there is a function of vitamin C in making enzymes that hydroxylate proteins like collagen, and
that's actually what the cause of scurvy was, and hydroxylating other proteins. And there may be
additional functions of this molecule we don't know about.

One of the things that is exciting to me about knowing the human genome is we finally have all the
puzzle pieces of life in one box and we have a chance of looking at those puzzle pieces and asking
how many of those different puzzles pieces genes products may be affected by vitamin C? We may have
some surprises, and what I would look for is in the immune system. It may be in certain individuals
higher levels of vitamin C tune up the immune system and when the immune system is turned up we can
go after the viruses.

Robyn Williams: Which also answers the aging question really. If you've got a strong immune system,
that's good all round.

Steven Clarke: That's exactly right.

Robyn Williams: Where will your work take you next on this?

Steven Clarke: What we are hoping to do here is to look now at new vitamin C synthesis pathways in
other organisms and how these other organisms may solve aging problems that way. One of the
organisms that's fantastic for aging research is a soil nematode, Caenorhabditis elegans, and with
this nematode...we can get some idea of the biochemistry of extending lifespan. A recent paper
suggested that with chemical modification you can extend the lifespan of these worms tenfold. Does
this mean human are going to live 1,000 years? I don't think so, but it may give us a biochemical
clue for that.

And one of the things that this work has taken us is back to the worms, and we're looking at a gene
product that's similar to the gene product that is involved in vitamin C synthesis in plants but
looks like it's probably not involved in vitamin C synthesis in these worms. So what is it involved
in? And that's what we want to go after. What we want to do is to try to look at the chemistry of
aging, what types of defences do we have to the fact that we're falling apart and the fact that
probably most of our functions are peaked at 16, 17, 18 and it's a slow downhill? How can we make
that downhill as slow as possible, to say...perhaps not a great lifespan, maybe we don't want to
live to 130, but we want a health-span. What we'd love to do is to live to be 95 and if at 95 we
drop dead, okay, we've been healthy.

Robyn Williams: The very young-looking Steven Clarke who's the director of the UCLA Molecular
Biology Institute, and professor of chemistry at the University of California Los Angeles.

Robyn Williams: And now something of a first. In the 33 years we've been bringing you The Science
Show I don't think I've ever brought you a scientist from Luxembourg. So today, a first. Carole
Linster who is a post-doc fellow working on vitamin C with Steven Clarke.

You're the first person, Carole, I've interviewed who is from Luxembourg. Which part of Luxembourg?
Or is it all the same?

Carole Linster: Well, for an American or an Australian it's probably all the same, but actually I
come from the capital of Luxembourg which is also called Luxembourg.

Robyn Williams: That's what I thought, that's what was slightly confusing. You had decided to come
to UCLA, where we are, talking about the vitamin C work with Professor Clarke, but you came for a
different reason, didn't you. What was it?

Carole Linster: That's correct. I was very interested in the aging research that Dr Clarke does
here, especially so the aspect of protein repair being involved in aging. Actually I came to study
this enzymatic mechanism, but through this research on aging they had discovered a gene that was of
unidentified function, and it turned out that it could maybe be involved in vitamin C synthesis.

Robyn Williams: And you happened to have been working on vitamin C in Luxembourg.

Carole Linster: That's correct. So my studies were not done in Luxembourg. I was born in Luxembourg
but my studies were done in Brussels where I did my PhD. I have been working during my PhD on the
regulation of vitamin C synthesis in animals actually.

Robyn Williams: And so when you came here you announced this and they decided to take your advice
to follow the vitamin C path.

Carole Linster: That's correct. Dr Steven Clarke found it a very good opportunity to use my
knowledge to maybe find out the secret about this gene of unknown function.

Robyn Williams: It's interesting that a senior scientist at a great university like this should be
so receptive to the ideas from a fairly young scientist like you.

Carole Linster: Yes, I think it's also a characteristic of Dr Steven Clarke which makes him a very
good group leader, I think. He trusts people and he just lets them discover. By trusting them I
think he gets out the best of them.

Robyn Williams: Congratulations on having your name on a major paper being published. But what was
your work specifically to do with they way the animals deal with vitamin C?

Carole Linster: That's the thing...actually I did my work in Brussels on vitamin C synthesis in
animals, but now when I came here this gene turned out to be important in vitamin C synthesis in
plants. So it is amazing but plants synthesis their vitamin C by a totally different pathway than
animals do, and there was still one major step that was not identified from an enzymatic point of
view. The gene that I talked about all the time happened to be the one encoding this missing

Robyn Williams: Interesting, isn't it. I thought that most animals get their vitamin C from outside
and their metabolism is really dealing with it to make the most of it.

Carole Linster: That's maybe a little bit incorrect because almost all animals are able to
synthesise their own vitamin C. Why we think that animals cannot is because the big exception is
humans. Humans cannot synthesise their own vitamin C, and that is true for other primates like
great apes and some other smaller animals too, but the majority of vertebrates can synthesise their
own vitamin C and they don't actually need a lot of vitamin C from plants, but we depend entirely
on plants for our vitamin C income.

Robyn Williams: I wonder why that happened?

Carole Linster: Yes, that's a little bit of a mystery of evolution. We have actually all the
enzymes responsible that lead to vitamin C synthesis but only the last, final, crucial enzyme is
missing in humans. It is there but it has become totally mutated, so as if sometime in evolution it
has been decided that it was not important, that we get enough from the outside and that we can
just not spend any efforts anymore on doing that.

Robyn Williams: Which is why we have to take so much vitamin C every day. By the way, how many
languages do you speak? You have perfect English and you obviously speak French.

Carole Linster: Yes, I speak English, French, German and Luxembourgish.

Robyn Williams: Luxembourgish is a different language as well.

Carole Linster: Yes, it is different.

Robyn Williams: It was charming to meet you. Thank you.

Carole Linster: Thank you.

Robyn Williams: That was Dr Carole Linster from Luxemburg, a country squashed between Belgium,
Germany and France with a population of just half a million.