Nature Podcast 20 April 2006

Introduction

This is a transcript of the 20 April edition of the weekly Nature podcast. Audio files for the current show and archive episodes can be accessed from the Nature podcast index page (http://www.nature.com/nature/podcast), which also contains details on how to subscribe to the Nature podcast for FREE, and has troubleshooting top-tips. Send us your feedback to mailto:podcast@nature.com.

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Chris Smith: This week: personalised medicine and what your urine says about you, a theory of snake evolution that seems to stand on its own two feet at last. We revisit Chernobyl 20 years after one of the world's worst nuclear disasters and lakes locked beneath Antarctica's ice sheet. Researchers watch from space as 2 cu km of water moves from one lake to another beneath the ice. Hello, I'm Chris Smith. Welcome to the 20th April edition of Nature's Podcast.Up first this week tailor-made medicine or pharmacogenomics. The whole idea is to personalise drugs and doses to the genetic requirements of the individual. But it turns out that it's a lot more complicated than that because other factors like age and nutritional status, and even the spectrum of bacteria living in the intestine, can all play a part in how drugs behave in the body. So how do we get around the problem? Well, Jeremy Nicholson from Imperial College in London argues instead that pharmaco-metabonomics is the way to go. In other words by measuring an individual's metabolic profile you can see the combined effect of their genes working together with the environment and, using that specific chemical signature, you can then predict that person's response to certain drugs or interventions. (Nature 440, 1073-1077; 2006)

Jeremy Nicholson: What we've found is a new approach to modelling individual variation in drug toxicity and drug metabolism. The interesting thing is that most drugs don't work in most patients so there's a quest now for personalised medicine, personalised healthcare. And that's really the Holy Grail of 21st century science, getting the right treatment for the right patient. And that has to be based on a knowledge of the biology of the individual. Metabolism captures both environmental and genetic influences on an individual so we've got a new conceptual approach to understanding individual variation which is to look at body fluid, metabolic signatures and, from these, trying to predict the outcome variation when you intervene with a drug.

Chris Smith: Now you've done this in animals. How would you see it mapping onto humans though?

Jeremy Nicholson: How I would see this going onto humans is an interesting question because humans are very much more metabolically variable. However, individuals vary in certain similar ways when they respond to a drug and what we're trying to do is find the metabolic needle in the haystack in all of that background variation.

Chris Smith: So talk us through the study you've done in your rats though, first.

Jeremy Nicholson: Well, what we did was we demonstrated that there is something in a metabolic signature that tells you about outcome. And we did it in two ways, a very simple experiment where we took a compound, galactosamine which is hyper variable in the way that animals respond to it – so some animals when you dose it with galactosamine have no effect and others get liver damage. And what we were able to show really simply was that animals that showed no damage and animals that showed extensive damage were metabolically different from the urinary profiles. And what we did then was design a much more extensive experiment using the commonly used analgesic, paracetamol, where we built mathematical models that linked metabolic variation prior to dosing to drug toxicity and extensive drug metabolism after dosing.

Chris Smith: If you did want to translate this to humans though, presumably you're going to need to give all these agents to the people first, work out what their metabolic profile will be on their urine and then you'll have a sort of gold standard against which to compare and relate these things?

Jeremy Nicholson: Yes. One day, a long way down the line, we will be able to do that. In the first instance what we have to do is to look at metabolic variation in drug metabolism so we can very easily dose people with low levels of sub-toxic drugs and build models that look at pre-dose metabolic signature in relation to the extent of drug metabolism. That is really easy to do. It will be possible in clinical trials to look at individual signatures before dosing and then, in the people that you actually find in clinical trials that showed some sorts of adverse drug reaction, you'll be able to say, well, of those people, what was it about them that was different in their pre-dose profile?

Chris Smith: And are there any other applications or spin-offs from this?

Jeremy Nicholson: Instead of looking for the adverse effects of the drug you could be looking for the positive effects of drugs. So you could be looking for what signature in a person's metabolic profile actually relates to really good outcomes, good response to drugs. And that's clinical efficacy optimisation which is at least as important as minimisation of toxicity in individuals.

Chris Smith: This sounds too simple to be true, though.

Jeremy Nicholson: Interesting point. However, irrespective of whether it's genetic or environmental influences, your body regulates itself by what goes out in the urine and those very subtle changes that occur in the urine metabolite profile are telling you about how the body manages itself on a moment to moment, or day to day basis. And that applies to any sort of intervention, at least in principle.

Chris Smith: With a name like pharmaco-metabonomics you'd be forgiven for thinking they were taking the proverbial. Jeremy Nicholson from Imperial College in London.

Chris Smith: And now to the origins of snakes. Did they slither out of the sea or evolve on dry land without ever getting their feet wet? Well now it looks like the latter's true because scientists working in Argentina have uncovered the 90 million year old remains of what they're calling Najash rionegrina. That's after the biblical snake that tempted Eve to eat the forbidden fruit and, as a result, he was condemned to a lifetime of slithering around on his belly. But what makes this fossil snake so important is that it has a pair of hind legs and, unlike the vestigial legs that are seen on some modern snakes, these legs are connected to the animal's backbone. (Nature 440, 1037-1040; 2006). Here's Nature's Mike Hopkin.

Mike Hopkin: Well in this paper in this week's issue of Nature by Sebastián Apesteguía and Hussam Zaher they are discussing a new fossil that I guess you could say gives a new definition to the term 'snake hipped'. It's the earliest ever snake found and, curiously, it had both hips and legs which gives a window into understanding exactly how these creatures evolved.

Chris Smith: What's the present theory of how snakes came to be anyway?

Mike Hopkin: Well, before this there were a couple of theories. One was that they originated as marine creatures; the other one was that they evolved on land and this, being the oldest and most primitive snake fossil ever found, seems to suggest that they came from land. And they had a fairly flat head at the front which the people who discovered it think might mean that it was good at burrowing or crawling, rather than swimming.

Chris Smith: And what does this new fossil look like?

Mike Hopkin: Well this would have looked much like a snake but with a sort of strange pair of little legs either side. It's a very long creature, as you'd expect. It had 122 vertebrae so it really would have looked like a very long slinky lizard, I guess.

Chris Smith: And those legs are actually connected up to the backbone with a proper hip structure?

Mike Hopkin: They are and that's what's surprising about this. It's the first time that that's ever been seen; obviously that was something that was lost quite early from snakes as they evolved.

Chris Smith: Have you any clues as to why it decided to give up legs?

Mike Hopkin: Well, that's a bit of a hazy thing. Obviously if it was living a life where it was crawling around on the ground and maybe delving into burrows that other creatures had dug as a place to take shelter, then maybe the legs would have gradually fallen out of use and evolution would have done away with them.

Chris Smith: So this makes this particular fossil pretty old and therefore snakes, as a lineage, pretty old as well?

Mike Hopkin: Yeah. It seems that snakes began their evolution journey back before the dinosaurs were wiped out. This is a fossil from the upper Cretaceous period which is actually the period that was ended when the meteor struck and destroyed the dinosaurs. So this is well over 65 million years old.

Chris Smith: Nature's Mike Hopkin introducing Najash, the most primitive snake yet discovered. And here's one of the people who discovered it, Sebastián Apesteguía.

Sebastián Apesteguía: Snake evolution took place about 150 million years ago and this snake is from only 90 million years ago so a big part of the snake evolution and history already occurred.

Chris Smith: So the legs were one of the last things to be lost?

Sebastián Apesteguía: Yes. Many snakes, especially constrictors, have legs still attached to their body but not really to the backbone. And this snake from Patagonia, this new snake, has very, very clear processes [?] in their legs and that's the difference because it shows not a reduced form but fully developed legs.

Chris Smith: Sebastián Apesteguía from Universidad Maimónides in Buenos Aires. Nature's Podcast, bringing the world of nature to life.In a few moments the little known field of Antarctic hydrology. But first, it's now 20 years since one of the world's worst nuclear disasters. And, talking to Anna Lacey, Nature's Mark Peplow considers Chernobyl's legacy two decades on. (Nature 440982-983; 2006; Nature 440, 984-986; 2006; Nature 440, 987-989; 2006; Nature 440, 993-994; 2006; Nature 440, 969-970; 2006).

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Mark Peplow: Thanks. Yes, it's 20 years ago this week that the Unit 4 reactor at the Russian Chernobyl plant blew up. It sprayed just under 7 tons of radioactive material into the sky and that carried as far as the West Coast of the UK. Now, scientists have been working to try and understand what the legacy of Chernobyl will be, both in terms of the health of people living very close to the reactor, the people who were in there in the first days trying to control the raging fires in the reactor core and indeed people living further away in Europe.

Anna Lacey: So how many people do they think have been affected by this disaster?

Mark Peplow: Well, that's the question that everybody wants an answer to. The Chernobyl Forum, which was a group made up of various UN agencies and the governments of Russia, Belarus and Ukraine, that group back in September last year came out with a report that pretty much gave a much lower number than we'd ever heard before: about 4,000 people expected to be killed outright by Chernobyl. But the way that the projection has been done really only takes into account the 600,000 people living closest to the reactor. So some people have argued that if you look at the whole of Europe that was affected that was about 600 million people; between 30,000 and 60,000 of those people could be expected to die of cancer induced by radiation from Chernobyl.

Anna Lacey: But it is not just a little bit too early to say just 20 years after the disaster, especially considering that we've been seeing effects from the Japanese atomic bombs in the War even 50 years later?

Mark Peplow: After the Nagasaki and Hiroshima bombs there was an enormous international research effort, very well coordinated to try and understand exactly what the effects of the radiation had been. And really, even though we're 50, 60 years after that, we are still learning exactly what the impacts of the radiation from those bombs was. And I think the same is going to be true of Chernobyl. In fact, in Chernobyl's case, I think the bottom line has to be that when you see predictions of how many people are going to die, really do be aware that those estimates come with a huge amount of uncertainty and it depends very much on which models you are using.

Anna Lacey: So all of this information coming out must be surely having an effect on nuclear waste disposal programmes across the world, not just Chernobyl?

Mark Peplow: Well this is the point that's been made many times by the International Atomic Energy Agency which is saying that if you look at the legacy of Chernobyl, overall the health and environment impact has not been anywhere near as great as people feared. But one of the major impacts has been, of course, in public confidence in nuclear energy. Nuclear power produces radioactive waste and this waste can last for tens of thousands of years; the question is what to do with it because, in some cases, you can reprocess it to extract the waste plutonium but of course plutonium is rather good for making nuclear bombs. So people are often concerned that this raises the risk of this material being stolen or being used to create rogue bombs, if you like.

Anna Lacey: So where are people going to put it?

Mark Peplow: At the moment one of the places in the States that's being looked at is a place called Yucca Mountain which is Nevada. It's thought to be one of the safest places in America to put spent fuel but, of course, people living in the area don't want it there. One of the most successful nuclear waste programmes has been in Finland. The key message seems to have been that rather than scientists and policy makers getting together and going, right, this is the best site, we're going to have it here, the answer in Finland seemed to be we need to get rid of this nuclear waste somewhere; we can offer incentives for communities that are prepared to host it on their land – who's interested?

Anna Lacey: But is there ever going to really be a big enough incentive to persuade people to have nuclear waste buried in their backyard?

Mark Peplow: It depends on how much incentive governments can provide. I guess the point is that, as the global mood changes and we learn more about climate change and people become informed about nuclear waste and nuclear power, I think there maybe more and more incentives for people to consider going down this path.

Chris Smith: Certainly a hot topic. Mark Peplow and Anna Lacey examining the issues of nuclear energy.

This is the Nature Podcast and the 20th April edition of Nature with me, Chris Smith. We've got a new feature to tell you about this week which is that we're now providing a full text transcript of each week's podcast. It's freely available from our website. You just click on the word text next to the show you're interested in on the Nature Podcast archive. You can find it at http://www.nature.com/podcast.

Now for our final story this week we're heading down to the South Pole where Bristol University's Martin Siegert has spotted some unusual watery movements beneath the Antarctic ice. (Nature 440, 1033-1036; 2006; Nature 440, 1000-1001; 2006).

Martin Siegert: Deep underneath the 4kms worth of the Antarctic ice sheet we've discovered that a sub-glacial lake has lost rapidly a large part of its volume and this water has moved over 200kms into another sub-glacial lake.

Chris Smith: How do you actually do it though? How do you know that water's moved around?

Martin Siegert: Well we looked at how the ice sheet surface changes and we had a satellite that was looking at the changes in ice sheet surface elevations and we noticed that one part of the Antarctic ice sheet lowered by three to four metres over a course of a year and 200kms away the ice sheet surface elevation went up by about a metre. And that's a very unusual change and there are very few alternative explanations for that amount of surface change in fact and actually, losing that amount of mass on the surface of the centre of East Antarctica, which is a very stabilised mass, it can only be the removal of something really rapid and all the alternatives point to it being water.

Chris Smith: Do you know what's driving that movement of water though, what's pushing it along?

Martin Siegert: Indeed. Well, the base of the eastern side of the ice sheet, much of it is at the pressure melting point so there's water being melted from the underside of the ice sheet and all this water will feed down into sub-glacial lakes where it collects. The sub-glacial lakes will be pressurising because water will be coming into them and the ice sheet will be attempting to hold that back and so that's an unstable situation: the ice sheet can't hold it back forever and, as the pressure increases to its threshold, the water will escape and so it outbursts.

Chris Smith: People are quite interested in those lakes, aren't they, for the simple reason that they're viewed as time capsules in the case of Vostok and similar bodies? Your work must therefore have those people quite worried?

Martin Siegert: Well, I don't know about that. It's actually only been ten years since a paper was published in Nature on Lake Vostok and really since then people were talking about these lakes as being very isolated distinct systems. And actually what we're identifying now is that maybe that's not the case and that will have to be revised. But it's still very exciting from a sub-glacial exploration point of view; I don't think it would harm the chances of getting to sub-glacial lakes or even belittle the types of science that could take place in those systems.

Chris Smith: The escape of so much water all at once, does that have any other consequences in terms of, say, salinity of the surrounding ocean, animal life, that kind of thing?

Martin Siegert: Well, we haven't shown that this water can get to the ice sheet margin but, even if it did, it is quite a large amount of water. It's 1.8 cu kms worth of water that we've seen transferred and actually that's a very small amount in terms of global ocean values and so it wouldn't have too much effect.

Chris Smith: Do you think climate change is having any kind of implication or bearing on what's happening here?

Martin Siegert: Well, I don't think so. The situation that we have is the underside of the Antarctic ice sheet. And remember, this is the East Antarctic ice sheet which is the stable part of Antarctica and there really isn't very much change going on there. What we think we've seen is a process which is common, both now and in the past. This is the first time that anyone's actually seen it.

Chris Smith: And what questions are you now gagging to answer on the basis of the intriguing observation you've got here?

Martin Siegert: Well, what we'd like to do is to find more of these processes, both in East Antarctica and in West Antarctica, because we know that a sub-glacial lake has lost mass and that water has flown underneath the ice sheet and into another lake. What we now have to try and do is understand the physics of the problem a bit better and that applies to getting more data, more observations, in order to constrain the system better than we have done up until now.

Chris Smith: Martin Siegert from the University of Bristol.Well, that's it for this week. In next week's Podcast we'll be getting to the heart of cardiovascular disease and also finding out why there are clouds gathering over Pakistan. But, in the meantime, if you'd like to find out a bit more about any of the stories we've been discussing this week, they're all available from our website at http://www.Nature.com/nature.

Production on this week's show was by Anna Lacey at Cambridge University and I'm Chris Smith.

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