Nature Podcast 17 August 2006

This is a transcript of the 17 August 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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Derek Thorne: Hello there, I'm Derek Thorne, filling in this week for Chris Smith. Coming up in this programme a close-up structure of an important component of bird flu could help us find effective treatments for the disease.

John Skehel: The structure of the N1 neuraminidase of H5N1 viruses shows a new cavity which might be used to develop new anti-influenza drugs.

Derek Thorne: Also, what's it like at the south pole of Mars?

Phil Christensen: Imagine standing on a sheet of ice a metre thick with geysers of gas exploding off all around you carrying dust into the atmosphere, that's Mars today.

Derek Thorne: And there's a new gene that could be critical for the evolution of the human brain, and scientists are desperate to find out what it does.

David Haussler: We'll put the gene in a mouse and see if it plays Mozart, but that experiment remains to be done.

Derek Thorne: You can find out what this gene is later in the show. But first, the emergence of H5N1 avian influenza is worrying for a number of reasons, and one of those is that the virus seems to have resistance against existing anti-viral drugs. Now, a team from the UK has some detailed answers on why these drugs aren't working, and their findings could help us find better treatments. The letters in the name H5N1 actually stand for haemagglutinin and neuraminidase and these proteins appear on the outside of the virus and are critical in the process of infection. The drugs we already have target the neuraminidase, but these protein molecules, also known as receptor destroying enzymes, vary from one virus to the next. Broadly speaking, they fall into two groups and while existing drugs target neuraminidases from one group, N1 falls into the other. John Skehel, of the National Institute for Medical Research in London, told Chris Smith about his team's x-ray crystallography study in which they worked out a detailed structure of the proteins in this other group.Nature advance online publication 442, (16 July 2006)

John Skehel: The receptor destroying enzyme, this is a neuraminidase that molecule so far has been targeted by antiviral drugs, Tamiflu, and Relenza. Now, the neuraminidases, they're divided into subtypes, and on that basis it turns out that there are nine subtypes of neuraminidase and 16 of haemagglutinin, and there are numerous combinations of haemagglutinin and neuraminidase of different subtypes in viruses that are abroad in the world infecting birds, largely.

Chris Smith: So what have you done to broaden the understanding of the problem?

John Skehel: Right, well, these nine subtypes of neuraminidase fall into two groups, and it turns out that the neuraminidases whose structures have been done before by x-ray crystallography, and those structures were instrumental in the design of Tamiflu and Relenza drugs. Those neuraminidases belong to one of the groups and the N1 neuraminidase of H5N1 avian virus, that's a member of the other phylogenetic group.

Chris Smith: Which hasn't had its x-ray structure solved?

John Skehel: That's right. So, that's what we've done, and we've done it also for two other subtypes in that group. There are four neuraminidases in that group, there are five in the other group but two of which have been looked at before. We've looked at three out of the four in this group, and one of them is the N1 of the current H5N1 virus.

Chris Smith: So, do the new structures highlight any new areas where we could potentially go in there and use that as a target for antivirals?

John Skehel: Yes. That's the main point. It turns out that unlike the previously determined structures, the structure of the N1, and the other members of this group, have a cavity next to the active site of the enzyme which might be able to be used to develop other drugs than the ones that are currently available.

Chris Smith: What sort of properties would that drug have to have in order to lock onto that cavity and block it up?

John Skehel: It'd probably be bigger. It turns out that in the Tamiflu, there's a six carbon ring, and it looks, at least from the structure, as if it will be possible to add more substituents which would then occupy the new cavity specific for this N1 group of neuraminidases, and in the first instance, those are the sorts of drugs you try to make.

Chris Smith: I suppose this is very pertinent at the moment because what we've seen with our limited exposure of these agents against the present H5N1 is that it seems to be able to become resistant quite rapidly.

John Skehel: Yes, that's right, and one of the things that our structures show is why they become resistant, what the significance of the amino acid substitutions are that make the things resistant.

Chris Smith: So how is that achieved?

John Skehel: Well, it's achieved by substituting amino acids in the active site which prevent the Tamiflu binding properly. And the hope would be that by making other compounds you'd be able to overcome the resistance to the already existing drugs.

Derek Thorne: John Skehel of the National Institute for Medical Research in London, whose research could lead to new drugs for avian influenza. Next, and staying with avian influenza, if we vaccinate birds in farms against bird flu, could it actually make a potential bird flu outbreak worse? This might seem like a strange question to ask, but it is an important one because vaccinated birds can still pick up the virus without showing many symptoms, and so an outbreak could last longer. Nick Savill of the University of Edinburgh and his team have developed a model to try and work out what this silent spread could lead to. Nature 442, 757 (17 August 2006)

Nick Savill: A lot of the debate about bird flu was whether vaccination would lead to increased risk of silent spread, so that's the transmission of bird flu between flocks and farm. And the argument at the time was that even if a bird is vaccinated it still has a small chance of becoming infected, and can shed small amounts of virus, but the clinical symptoms might not be apparent. So, vaccination could make matters worse, not better. We're interested to have a look at it. Surprisingly, I actually couldn't find any reference to silent spread in the literature nor any support for this argument, so that's why we decided to investigate it for ourselves using mathematical modelling.

Chris Smith: So how did you actually build the model given that there's very little existing literature in order to make the model faithful to the real situation?

Nick Savill: We took a lot of advice from DEFRA and bird flu experts around the world to come up with a model and to parameterise the model, and we came to the conclusion the best way was to use an individual base model, which means that we're modelling each and every bird in the flock, and each bird has a set of parameters associated with it. For example, its latent period, its asymptomatic period, how infectious it is, how much infectious faeces it produces, what its chance of actually becoming infected is, and so on.

Chris Smith: So, with the model as it stands, what are the implications? What would be the predictions about how we should go forward from this point?

Nick Savill: The implications are that if you want to vaccinate your birds, you've got to make sure that you vaccinate as many of them as possible. You really want to vaccinate almost 100%. If you're vaccinating 80% then you're going to run into trouble because it's going to take longer to detect bird flu in flocks and the implication is that more infected faeces is accumulating in the environment, so generally the flock is more infectious to other flocks. But, also, outbreaks may be undetected at the end of the production cycle, and this is a particularly critical time for transmission between farms because that's when bio-security tends to break down, as birds are moved out of barns and into cages and the barns are cleaned and disinfected. So, it's quite a critical time at the end of the production cycle, and so the more birds you vaccinate, the longer the outbreaks occur, you're likely to get undetected outbreaks at the end of the production cycle, and that increases the chance that you're going to get silent spread between farms.

Chris Smith: So, the bottom line is that you vaccinate everybody, or you vaccinate nobody, because otherwise you're actually potentially sweeping the problem under the carpet?

Nick Savill: That's exactly correct, yes, unless, of course, you use unvaccinated sentinel birds to detect the virus much more quickly. Because they're unvaccinated they're much more susceptible to disease and so you can actually see them dying and you can detect it much quicker in the flock.

Chris Smith: So what would be your recommendations tomorrow if you were asked on the basis of what you've found to guide farming and poultry policy in the UK? What would you suggest?

Nick Savill: Well, our recommendation would be that, if you're going to vaccinate make sure you do it extremely well, but more importantly, use unvaccinated sentinel birds and monitor them very carefully.

Derek Thorne: Nick Savill from the University of Edinburgh with some important advice for any Government that wishes to carry out bird flu vaccination. Now, it's time to hear about some of this week's major science news stories. Here's Anna Lacey talking to Nature's Alex Witze.

Anna Lacey: In the 12th January edition of Nature, Frank Keppler and his colleagues from the Max Plank Institute in Germany revealed a new source for the potent greenhouse gas, methane Nature 439, 187–191 (12 January 2006) . But, surprisingly, the culprit wasn't manmade. Every year 62 to 236 million tons of methane seemed to be being produced by plants. To comment on what's happened since this discovery, here's Nature's Alex Witze. Nature 442, 730–731 (17 August 2006)

Alex Witze: That discovery really startled a lot of people because it didn't make sense to them that living plants could be giving off methane, and a lot of researchers have been scrambling over the past seven months to try and figure out whether, in fact, those findings are right. There were a lot of questions initially about the work because the scientists looked at a couple of individual plants in the little chamber, and trying to extrapolate those measurements from a couple of plants in a laboratory up to the entire global methane budget is kind of a challenge.

Anna Lacey: Science is all about trying to prove or disprove people's theories, but why are they so keen to look at this data again?

Alex Witze: Because methane is one of the really big greenhouse gases. It's about 20 times more powerful a greenhouse gas than carbon dioxide. There's much less of it than carbon dioxide but knowing how much there is and where it comes from, how much humans are producing as opposed to other sources such as these plants, is really critical for people who are trying to figure out how much greenhouse gases there are and where they're all coming from.

Anna Lacey: And so what are people finding when they're trying to replicate these experiments?

Alex Witze: There's been a mix of results. Most of them seem to indicate that there may not be quite as much methane coming from plants as the original paper indicated. There have been a couple of studies that support the numbers that he was coming up with, but most of them seem to suggest, yes, there is an effect, it may just not be quite as big as we had thought originally.

Anna Lacey: When this paper came out this really made people look again at what was producing methane, and the contribution of plants. But now people are doubting it in certain ways. How is this going to affect what people might be doing about climate change policy, for instance?

Alex Witze: I think perhaps this will signify to politicians that it's one more thing they have to have on their plate. I don't think anyone's going to go back to the drawing board and re-evaluate the Kyoto Protocol on climate change, for instance, but they realise that as they go forward they need to always keep this in mind and start to incorporate it as some of the data comes in, and as scientists start to agree on what exactly is happening.

Anna Lacey: Well, now let's move on to a mass migration that's going on in the US at the moment, from the West Coast to the East Coast. Nature 442, 729 (17 August 2006)

Alex Witze: Yes, there is a big push by the state of Florida, actually. One of the largest states in the country, of course, that's run by President Bush's brother, Jeb. He's gotten a lot of money from the State Legislature to invest in a high-tech type jobs, so he's been sending people out to California to try and recruit some of the big high-name biomedical and other research institutes to come to Florida and open up branches there.

Anna Lacey: But why California? There must be other good institutes across the US?

Alex Witze: Yes there are a lot of good institutes around the country, of course, but Florida is targeting California in particular. They have kind of a history. There's the Scripps Research Institute which is one of the big biomedical research institutes in California. Over the last couple of years Scripps and its Florida branch have been very involved in getting a lot of money from the state and because they've had this ongoing relationship with Scripps, I think they're pretty much going back to the same town in southern California and saying, hey, who else can we get to bring out here?

Anna Lacey: So how much money are we talking about here?

Alex Witze: It doesn't sound like a whole lot. It's about $245 million US, but those are basically incentives just to get people out there. So, these are obviously wealthy research institutes with a lot of money and Florida is hoping that if they can get them set up it'll essentially jumpstart the economy in Florida, and essentially just becoming more of a research powerhouse, to try and grab a little bit of that glory from states like California that have been leading states in the country.

Anna Lacey: But how are the other research institutes in Florida taking this? Surely this is money that they would hope would be coming their way, not some California institute?

Alex Witze: Yes, that's an excellent question, and I think we'll just have to see how things develop. There's a lot of money out there and a lot of people competing for it and we'll see who ends up winning in the end.

Derek Thorne: Nature's Alex Witze speaking with Anna Lacey. Nature's podcast bringing the world of nature to life. Still to come in this programme, we may have to rewrite the text books when it comes to the nitrogen cycle, and what is the fastest evolving gene in the human genome and what does it do? But first, let's take a trip to the south pole of Mars which is far colder than our own South Pole; so cold, in fact, that the icecaps there are made from solid carbon dioxide. Two papers in this week's Nature have shed some light on some black dots which appear at a certain point in the Martian year. Chris Smith found out more from Phil Christensen of Arizona State University. Nature 442, 793–796 (17 August 2006)

Phil Christensen: Mars has solid CO2 icecaps that grow in the winter and shrink in the summer, and we noticed some very unusual dark spots that were forming on these caps early in the spring, and we've struggled now for five or six years to try to figure out what they were. Some people thought that it was just the ice going away and exposing dark sand underneath, but what we discovered, we have an infrared camera in orbit that can measure the temperature of the surface, and what we found is these dark spots, instead of being warm like you would expect if they were dark sand, they were still at the same temperature as if they were carbon dioxide ice.

Chris Smith: So it can't be the surface showing through then?

Phil Christensen: They cannot be the surface showing through, and so it's something that must be some dark material that is somehow sitting on top of the ice. In order to explain that we ended up having to come up with a very complex model. It's a process that just doesn't happen on the earth. There is nowhere you could go to the earth and find this, and the closest thing we can say to explain is these are geysers of carbon dioxide gas that's exploding out through vents and carrying sand up into the air with it, that then falls back down on the ice so that you get this dark sand on top of the ice.

Chris Smith: So why have you got some kind of geyser coming out from under the ice? Why is it not just sublimating from the surface where the sun is?

Phil Christensen: What we've come up, the model we have is that this ice, this metre of ice, it's not snow and frosty material; it's actually a solid slab of ice. So, if you were standing on it you could see to the bottom, you could see through this ice that extends for hundreds of kilometres in all directions. The sunlight goes through that ice, hits the bottom of the dirt, warms up, and actually sublimates the ice from the bottom, so the pressure builds up underneath this slab and eventually ruptures through the slab to form these jets of gas that go rocketing up and carry the sand up into the air which then falls down on the top of the ice.

Chris Smith: I suppose the only way you're going to know for sure is if you can physically go there and take a look?

Phil Christensen: That's true. One of the things we've been trying to do, we've been imaging some of these areas almost every day now for a year in the hopes of actually catching one of these geysers in action. We have a couple of tantalising pictures which we're still working on where we might actually see evidence of these geysers in action. But, we can't quite prove that yet. But, you're right, it'd be great to have some corroborative evidence that this process is really going on.

Derek Thorne: That's Phil Christensen from Arizona State University. And this week's Nature features another paper looking at the black dots but from a slightly different perspective. Here's Yves Langevin from the University of Paris 11. Nature 442, 790–792 (17 August 2006)

Yves Langevin: We measured the reflection of the surface in many wavelengths in the near infrared, with an instrument called Omega, and what we found out is that this is not a clear slab of CO2 ice. On the contrary, there is a lot of dark dust at the very surface of CO2 ice, and that's a completely new view of this very bizarre region which is called the cryptic region.

Chris Smith: How do you know the dust is on the top and not, say, in the ice or underneath? How does your instrument work that out?

Yves Langevin: Our instrument is able to observe absorption lines which are created by CO2 ice, so if sunlight travels any distance, even a few millimetres within CO2 ice, we see very deep absorption bands of specific wavelengths, and this is not the case. We see very shallow absorption bands, so that means the sunlight is not able to get far into CO2 ice which means it must meet something on the surface which has to be dust.

Chris Smith: Now that ice comes and goes, doesn't it, seasonally on Mars? So, with that in mind, does this mean, then, that something is moving dust around on the surface of Mars and putting it on top of the ice?

Yves Langevin: Definitely, yes, and you have two solutions. Either the dust comes from below CO2 ice, because you have bubbles of gas which are forming just at the boundary between CO2 and the actual surface, and these bubbles burst and bring dust to the very surface. The other possibility is that you have, close to this region, northwest of it, a very large basin which is called Hellas and this basin completely dominates wind patterns close to the southern polar cap. So these wind patterns which come in from Hellas could bring in some dust which could settle on CO2 ice specifically in this region.

Chris Smith: So that clears that puzzle up to a certain extent, but in what way does it add to our overall knowledge of how the weather and the seasons work on Mars?

Yves Langevin: Well, first of all it should be noted that these seasonal caps play an absolutely major role in the climate of Mars. About 40% of the atmosphere actually condenses on each pole during each winter, and some smaller fractions of gases, such as water vapour, all of it goes into the final cap. So, understanding very precisely how the seasonal caps come and go is absolutely vital for understanding the climate of Mars.

Derek Thorne: Yves Langevin from the University of Paris 11 who's been investigating the black dots that appear around Mars' south pole.You're listening to the Nature podcast from 17th August edition of the journal. I'm Derek Thorne. If you'd like to learn more about the stories featured in this week's programme, please go to our website at http://www.nature.com/nature. And if you have any comments on this or one of our previous podcasts, you can send us an email to mailto:podcast@nature.com. And also this week, Nature is running a special web focus called New Horizons in Cancer Research. The focus includes the latest articles and letters on the role of stem cells in cancer development, three news features one of which asks if mice are too mouse-like to be effective human models when looking for new drugs, and a summary of how far we have come, and still have to go, to cure cancer. The New Horizons in Cancer web focus can be found at http://www.nature.com/nature/focus.Next, scientists might have to rethink the details of the nitrogen cycle which is the natural process by which nitrogen is used and then recycled. One of the key steps of the cycle is oxidation of the nitrogen compound, ammonia, and scientists originally thought that bacteria in the soil were mainly responsible, but it now seems the main players might be archaea, a very distinct set of single cell organisms that are typically associated with extreme environments. Talking to Chris Smith, here's Christa Schleper of the University of Bergen. Nature 442, 806–809 (17 August 2006)

Christa Schleper: We have discovered high amounts of ammonia oxidising archaea in various pristine and agricultural soils over Europe, and they outnumber, in all cases, the groups of bacteria that have so far been known to perform this process.

Chris Smith: But what are these archaea and why are they important?

Christa Schleper: These archaea are a group of prokaryotes that are very different from the well known bacteria, and they were so far famous for being extremists living in extreme environments and only with molecular techniques it has been found that they are also quite abundant in moderate, commonplace environments like soils and marine.

Chris Smith: From an evolutionary point of view, how do they fit into life's rich tapestry?

Christa Schleper: They form the third domain of life and they are as distinct from bacteria as they are from eukaryotes, so plants and animals.

Chris Smith: And so their normal role in the environment and their contribution to soil biology is exactly what?

Christa Schleper: We have found recently, and also some other groups, that some of them seem to be ammonia oxidisers, and this means that they would plan an important role in the nitrogen cycle on earth by oxidising ammonia to nitrite.

Chris Smith: So do they serve to enrich soil or do they actually do the opposite?

Christa Schleper: This is a delicate process. It actually serves to enrich the soil because by oxidising the ammonia it becomes more available to plants, but there is also a negative side to it because it means that nitrogen compounds are washed out more easily from the soil when it rains. For example, if it's sandy soil the nitrogen gets lost quite easily to the ground water.

Chris Smith: And how does their number vary in different types of soil because the world is covered in many different types of soil, some of which have been farmed and some haven't?

Christa Schleper: Yes, we actually find an astonishingly even numbers of archaea in all these various soils whereas the bacteria counterparts which are in lower numbers, they vary also more frequently, so the archaea dominates by 2:200-fold, approximately, over the bacteria.

Chris Smith: So why is it that the bacteria seem to be affected by, say, fertilisers and different soil types, but the archaea don't?

Christa Schleper: We don't know yet. It might just depend on the versatility of their metabolism, on their dependence on oxygen or other components.

Chris Smith: So does this finding mean we're going to have to essentially rewrite the biology books of the nitrogen cycle because previously everyone thought it was down to the bacteria, didn't they?

Christa Schleper: Yes, that's very true. It might actually need to be rewritten, but first of all we have to prove that these archaea are also more active with respect to ammonia oxidation. At the moment we know they are more abundant at least and they are also transcriptionally active, so we really assume that they might be the most important group in nitrification.

Chris Smith: So how did you find them in the first place, and how did you do this study specifically?

Christa Schleper: We first found these genes for ammonia mono-oxygenase by metagenomic studies, and now we quantified this gene by qualitative polymerase chain reaction and we also used a novel technique; high-throughput para-sequencing on cDNA libraries, for example, from soil.

Chris Smith: What are the implications of what you've now found, apart from obviously rewriting text books?

Christa Schleper: Ammonia oxidation is an important step in the global nitrogen cycle and it's relevant of course to know the major groups of organisms that perform ammonia oxidation, so that one can learn to influence their activity, not only in soils but also, for example, in waste water treatment plants where nitrification also plays an important role to clean the water for example.

Derek Thorne: Christa Schleper of the University of Bergen explaining how our current version of the nitrogen cycle isn't quite right.And, finally, the human genome must have evolved in some important way since our species separated from our ape ancestors. For one thing, our brains are far better developed and so there must be some genes which were responsible for that change. Well, this week's Nature features some fascinating insights into which parts of the genome have been changing the fastest, and among the findings is a newly discovered gene which could play an important role in the brain. With the details here is David Haussler from the Howard Hughes Medical Institute in Santa Cruz. Nature advance online publication August 2006

David Haussler: We looked for regions of the human genome that were meticulously guarded from changes over the last hundred or so million years, and then suddenly reworked in the last five to seven million years, since we split ways with our common ancestor, with chimp.

Chris Smith: How did you actually do that? How did you manage to home in on those areas that had remained stable for a long time and then suddenly changed?

David Haussler: This was a computational scan and we took advantage of the genome sequences that the human, the chimp, mouse and rat and other mammals, primarily, by comparing these genome sequences we could zero in on the regions that were stable for a long time and then changed suddenly in the human lineage.

Chris Smith: And these are presumably genes which enabled our brains to expand in certain areas in a very pronounced and profound way?

David Haussler: Well, first of all, 98.5% of the human genome doesn't even code for protein. Most of it is what some people would call junk DNA, and secondly, a lot of very good scientists had already looked for regions like this in the genes, so we call these regions 'human accelerated' regions. They're regions that were highly conserved by negative selection for a long time and then accelerated just in the human lineage. And, the ones in the protein-coding regions have been pretty picked over, so we actually didn't expect to find many more there. We were hoping to find them in the non-coding DNA, and we did. We found 49 regions that were statistically significant.

Chris Smith: So if this is happening in a non-coding region, what actually is that non-coding region doing?

David Haussler: That is, of course, the mystery and the answer is, we don't know for most of these regions, at this point. But the most dramatically changed region we have determined is a gene, but it's not a protein coding gene, it's a gene that makes a structural RNA sequence.

Chris Smith: And what was the gene?

David Haussler: It's a previously completely unstudied gene. No one knew it was there before we stumbled upon it. This is an interesting way to find a gene, so we named it 'human accelerated region 1', or HAR1.

Chris Smith: So what actually is HAR1 and where is it expressed, and what does it do? Have you got any clues to that yet?

David Haussler: We found some evidence from expressed sequence tags from some high throughput sequencing enterprises that it is, in fact, expressed in the brain, but we had no clue what the specific expression pattern was until our very good colleague, Pierre Vanderhagen, showed up one day. Now, Pierre studies the development of the visual system and he was excited to hear that we had found a gene that was the most fast-evolving gene in the human genome and seemed to be expressed in the brain, so we convinced him just to see if there was any specific expression pattern.

Chris Smith: So where is HAR1 expressed? Where do you find it?

David Haussler: We find it right at the position in the development of the brain in which the cerebral cortex is first being formed, and working with Pierre we want to knock it out in a mouse, and of course we also want to replace the mouse version of the gene with the human version of the gene and see how that affects the mouse development.

Chris Smith: It sounds extraordinary. You could get an exceedingly brainy mouse.

David Haussler: Well, it's not clear that mouse is going to start playing Mozart, but we'll look to see if there's any affect that we can measure in the laboratory from this.

Chris Smith: David Haussler from the Howard Hughes Medical Institute in Santa Cruz who is hoping to uncover the role of the fastest evolving gene in the human genome.That's all for this week, so thank you for listening, but do join us next time when the humble worm will divulge some of the secrets of its inheritance, and we'll learn that some micro-organisms prefer to choose their friends.The Nature podcast is produced in the Division of Virology at Cambridge University by Anna Lacey, myself Derek Thorn and Chris Smith, who returns next week.AdvertisementThe Nature podcast is sponsored by Bio-Rad, at the centre of scientific discovery for over 50 years, and on the web at http://www.discover.biorad.com.