Nature Podcast 31 August 2006

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Chris Smith: This week, new insights into what makes males infertile and how to make better contraceptives.

Barbara Meyer: Our list of proteins that are important for sperm production in the worm provides an excellent opportunity to identify causes of male infertility and targets for male contraceptives.

Chris Smith: We'll be finding out why size really is important, at least when it comes to the end of the stars life.

Paulo Mazzali: In the context of stars blowing up, size really matters. If you're a very very massive star you can generate real firework. On the other hand, if you're not very massive you can still do something.

Chris Smith: And we have a report of the first glimpse of that very process taking place.

Sergio Campana: Each gamma ray burst is a peculiar supernova and for the first time we are looking at a star in the act of exploding.

Chris Smith: And we'll also be hearing how RNA interference technology can have far reaching consequences for an animal's offspring, as far reaching, in fact, as 80 generations down the line.

Ronald Plasterk: You can silence a gene by RNA interference and it will remain silenced for over 80 animal generations.

Chris Smith: More on all of those stories coming up shortly. Hello, I'm Chris Smith, and welcome to this week's show. First today, how the humble worm C. elegans, has helped Barbara Meyer to come up with the most comprehensive map yet of the key proteins that contribute to male fertility and, potentially, a male pill. Nature advance online publication 30 August 2006

Barbara Meyer: We've been able to identify a host of new proteins that are important for sperm production in C. elegans and, remarkably, these sperm proteins are conserved in mouse and humans and in mouse and humans they're also important for fertility.

Chris Smith: How did you do it?

Barbara Meyer: Our first goal was to discover proteins involved in very basic sperm processes like compacting sperm DNA, segregating the DNA in preparation for making the sperm. So Diana Chu, who is initiating the studies in my lab, made chromatin preparations from the sperm and she also isolated chromatin from oocytes and collaborated with John Yates's lab at Scripps to identify all the proteins in both those two samples. Her idea was that proteins that were unique to sperm and not found in the oocyte might give us a unique handle on proteins important for the processes that makes sperm uniquely sperm. She was able to identify over 1,000 proteins from the sperm and over 800 proteins from oocytes and by the time she subtracted the oocyte protein from the sperm proteins, she was left with a mere 132 proteins that were sperm specific or sperm enriched. And, starting with that set, she was able to look at the consequences in the worm of disrupting the gene that encoded that protein.

Chris Smith: And what was the result when you did that?

Barbara Meyer: She found that over 50% of the genes that she disrupted, in fact, caused sterility of embryonic lethality so, in fact, the proteins that she had discovered were indeed important for fertility.

Chris Smith: So you can be reasonable sure that that's a robust finding but how does that map onto, say, bigger animals, mice, humans, that kind of thing?

Barbara Meyer: Over 30% of the genes that were knocked out in the mouse caused mouse male fertility problems so that automatically validated Diana Chu's study that the proteins she had discovered from the worm are, in fact, their homologs are in fact important for fertility in the mouse.

Chris Smith: Do any of them map onto established human genes that have been linked to infertility in us?

Barbara Meyer: Yes they do. There are very few genes that have been discovered in humans that are the root cause of male infertility but there are a few and, of the two that are known, the C. elegans genes map out to the human gene. There's a topoisomerase that is responsible for some human causes of male infertility and there is a candidate gene in the human genome that's a helicase that's thought to be required for male fertility. It hasn't been proven that's the case but, as it happens, one of our helicase genes is very similar to that gene and our study makes it all the more likely that the gene that the human geneticists are homing in on is, in fact, the real gene responsible for human infertility.

Chris Smith: Is that where you're going to go next with the study to try and find out whether some of these genes are amenable to some kind of therapy?

Barbara Meyer: One of the original conceptions of this project was to hope that some of the genes we would identify could actually be the targets of either safe contraceptives or finding genes that were important for human fertility, but really our thought was that once this list was available to the scientific community, those people working in the mouse and in humans would have a rich database to look through and address whether or not the genes they're been studying, in fact, might be the same genes that we were studying. So we view this as a community service, in a way, that provides a huge list of information for many people out there whose main projects are to look at human infertility.

Chris Smith: Barbara Meyer from the University of California Berkeley, explaining to me how she and her colleges have used the nematode worm, C. elegans to pinpoint sperm specific proteins that might hold the key to the next generation of contraceptives and also new avenues for infertility research. Now from the head of a sperm to the head of a monkey and how the brain learns to categorise information. Harvard's David Freedman has found a population of nerves cells in the brain's lateral intraparietal area, or LIP for short, which seems to be involved in learning how to put visual information into different categories. For instance a straight line versus a wiggly line. Nature advance online publication 27 August 2006

David Freedman: The activity of a part of the brain called the posterior parietal cortex plays a role in learning and encoding the category or meaning of the things that we see, so what we did is we taught subjects to play a type of computer game in which they learn to group visual patters into two categories and then, after they learned to play this computer game, we monitored their brain activity while they're playing the game and found that parietal cortex activity encoded the category membership of the visual patterns rather than encoding differences in visual features between patterns.

Chris Smith: And this is in monkeys?

David Freedman: In monkey's, that's right.

Chris Smith: So, this is relevant to humans?

David Freedman: Exactly, monkeys are an excellent model for studying human behaviour and the function of the human brain because our brains are very similar.

Chris Smith: So what was the actual task you're getting them to do and how is it designed in order to flush out this linkage between neurons which encode the role of something versus just it's identity?

David Freedman: We trained monkeys, over the course of just a few weeks, to categorise moving, visual patterns and these visual patterns can move in any of 12 directions, you can imagine the 12 directions around a clock face, and what we trained them to do is to group those 12 directions into two discreet categories, or two discreet groups, so that six of the directions belong in one category and the other six directions belong in the other category and then, once they learned this category scheme they performed a simple matching task, so what they had to do is to just respond when two patterns were in the same category.

Chris Smith: And how do you record when they've learnt that task and how these neurons pick up and do the categorisation?

David Freedman: Well, we're able to record the electrical activity of individual neurons in the brain and these are the electrical signatures of neurons in the brain communicating with one another and so we're able to record these electrical signals and then, later, analyse the patterns of electrical signals to determine what kind of information is encoded in the electrical activity from different brain areas.

Chris Smith: So before they actually starting learning the task, how did the activity in those neurons compare with how it performed after they'd learnt to do this?

David Freedman: Previous studies in this brain area have shown that these neurons do respond to moving visual patterns but they don't encode anything explicitly related to the category of those motion directions and this is in monkeys that have never learnt to categorise anything. But once the monkeys learnt to categorise these visual patterns suddenly these neurons show very strong and robust encoding of the category membership of those motion directions. So through that process of several weeks of learning we suspect that these neurons are undergoing dramatic changes in the way that they process these visual features.

Chris Smith: So what are the implications to learning in general, on the basis of what you've found?

David Freedman: Most categories, of course, are learnt. We're not born with knowledge of categories like chair or table, instead we learn to group items like this into meaningful categories through our experience with the world and this is an important process because it allows us to make sense of the world around us and to behave appropriately in response to our surroundings. So by studying categories it's a way to, hopefully, tap into the neural mechanisms that apply to all types of learning.

Chris Smith: Harvard's David Freedman who, together with his colleague, John Assad, has found a population of nerve cells in the brain's parietal cortex that learn how to categorise visual information. Nature's Podcast, bringing the world of Nature to life. Coming up shortly, why size matters, at least if you're a dying star and how RNA interference can help to silence genes for generations? First though, with news of the SMART-1 moon mission, here's Anna Lacey. Nature 442, 969 (31 August 2006)

Anna Lacey: In a few days time SMART-1, a spacecraft sent up to monitor the moon, will be making a spectacular crash landing into the lunar surface. Nature's Mike Hopkin went along to a special session to find out what the three-year mission has managed to uncover. So, Mike, tell us what's SMART-1 all about?

Mike Hopkin: Well, a lot of the reason behind was as a test bed for new technologies for interplanetary travel and it was the first mission to fly anywhere using an ion drive, which sounds a bit of a Star Trek idea, but it's supposed to be the future for travelling long distance. Once it was there, the idea was to map the moon in unprecedented detail which will help in working out what the rocks are actually made of and whether the Apollo lunar rock samples are representative of the whole place. After it's done all that, and it's really been very successful, the only thing left is to crash land it so I went to a special meeting just to find out what that's going to be like and Manuel Grande, one of the project scientists at the University of Aberystwyth told me what we can expect for splash down.

Manuel Grande: If you think about something rather like a washing machine which is flying about five times as fast as an aircraft normally lands, at about the same angle, so coming into land on a runway which is not concrete but is rubble and dust and sand, that's a pretty good mental picture and you can imagine that that's not exactly a soft landing but is a long way different from a meteorite impact.

Anna Lacey: That was Manuel Grande from the University of Aberystwyth, talking about the lunar impact but Mike are we actually going to be able to see this impact?

Mike Hopkin: Well, in terms of amateur astronomers looking out for it, you'll have to be quite serious. Anyone armed with a decent pair of binoculars will only be able to see dust and rocks that fly up more than about 20 kilometres above the lunar surface, they'll have to fly that high in order to get into the sunlight above the nearby mountains. But should that happen, and they reckon perhaps 1% of the stuff that's kicked up in the impact will rise that high, you'll be able to see it around North America, the west part of North America and Hawaii and also down in parts of South America. It will happen at about quarter to six am, universal time, on Sunday morning which, if you're in that part of the world, will be late Saturday night.

Anna Lacey: As you were saying a little bit earlier, one of the purposes of is mission was to actually take some photos of the moon and find out what it looks like, have we actually discovered anything new about it?

Mike Hopkin: Well, one of the interesting things they found was what they call some peaks of perpetual sunshine which, because the moon, like many other planetary bodies, is slightly tilted, some certain places of high elevation, so it's some peaks near the North Pole of the moon actually never dip into the shade at all, at any point during the moon's cycle. So that will obviously be a good place to put solar power generators and things like that, that we might need if we're going to set up any kind of base on the moon. And the whole idea of moon colonisation, obviously of which that is a first step, is something that a lot of farsighted scientists are already thinking about. Professor Bernard Foing of the European Space Agency, who is another of the scientists behind the mission, told me a bit more about what would be involved in moon colonisation.

Bernard Foing: Actually the moon is a place where we have the challenge – can we settle there, can we live off the resources from the moon, are there some best places to be? We have found, with SMART-1, some area near the North Pole which is to be in permanent sunlight, even in winter, so that's a place where I would like to go so I could live with solar power.

Anna Lacey: But will having energy like this, from solar power, actually solve the other problems of living on the moon such as there isn't enough gravity?

Mike Hopkin: Well, I think the gravity is probably one of the minor issues actually. I mean the men could walk on the moon when they went up there with the Apollo landings. Probably a more pressing concern, once we figure out the oxygen, is getting enough water and making plants grow there, which means that we could then use the plants to feed animals and, sort of, build up a sustainable food economy there. The Japanese have declared that they want to start looking at how to build a moon base by about 2030 so it looks like, in the longer term, the world's space agencies might be getting together to try and look at a lunar base within the next, maybe even, 20 years and then from there that could be a staging post towards Mars and further out into the solar system, hopefully.

Chris Smith: This is Nature's podcast from the 31st August edition of Nature and I'm Chris Smith. If you'd like to read a bit more about any of the reports we are covering this week, they're all available from our website at http://www.nature.com/nature and if you are on line and you'd like to drop me a line about this, or one of our previous programmes, then please email your feedback to mailto:podcast@nature.com and now to the world of gamma ray bursts, or GRBs, which are intense flashed of light produced by the deaths of massive stars as they explode in a supernova and collapse to produce a black hole. At least that's what we thought, because now Paulo Mazzali and his colleagues from the Max Planck Institute for Astrophysics in Garching, Germany have used the Swift satellite to track down softer bursts of energy in the x-ray spectrum which are also associated with the supernova. Nature 442, 1011–1013(31 August 2006), Nature 442, 1018–1020(31 August 2006), Nature 442, 992–994(31 August 2006)

Paulo Mazzali: An x-ray flash is a weak equivalent of a gamma ray burst. They're weaker in energetic output and they're softer in spectrum. It has been known, for a long time, that supernova are associated with gamma ray bursts. It was not clear that x-ray flashes were themselves associated with the death of massive stars. So what we have discovered is that there is a supernova associated with an x-ray flash and we have done some analysis work to understand the properties of the supernova and of the star that caused it.

Chris Smith: But how did this burst differ from a more normal GRB? Caltech's Alicia Soderberg and her colleagues looked at the energetics at the event. Nature 442, 1014–1017 (31 August 2006) , Nature 442, 992–994 (31 August 2006)

Alicia Soderberg: These observations have enabled us to show that this event is unlike other gamma ray bursts in the sense that it's 100 times less energetic. Most of the gamma ray bursts that we've observed and studied have all been nearly standard energy, they all have about 1051 erg omitted at part of the explosion. This event, however, has significant less energy and the question is why has this happened and does it have to do with the difference in the progenitor?

Chris Smith: Well Paulo Mazzali thinks that is does and that very large stars produce classic gamma ray bursts whilst their smaller counterparts emit x-ray flashes.

Paulo Mazzali: In this particular case we think that the reason the x-ray flash was an x-ray flash rather than a gamma ray burst is that the star was not massive enough to collapse to a black hole, but it only collapsed to a neutron star, so the energy available to make a high energy transient was not as high as in the case of gamma ray bursts.

Chris Smith: So it looks like x-ray flashes may be much more common than we thought previously, but why have we missed them in the past and what's the next step?

Paulo Mazzali: Gamma ray bursts are stronger in energetic output, they're easier to detect and therefore they can be seen at much larger distances. Now these events aren't very frequent, I mean, they only happen very rarely in a single galaxy so if one has a chance to look further because the event is brighter, then you have a much bigger number of events to pick up. In the case of x-ray flashes these are apparently weaker and so it's much less frequently do you get an event that's sufficiently nearby that you can follow it. We need to work hard at discovering more x-ray flashes and follow them up and, hopefully, discover supernovae there and draw the line between the x-ray flash supernova association and the GRB supernova association to see whether there is a continuum of properties or whether they are different events and, first of all, to confirm that there is a linear correlation between the energy of the hard event and the properties of the supernova.

Chris Smith: But what are the other implications of these findings and what other questions remain to be answered? Alicia Soderberg again.

Alicia Soderberg: The implications are that there's actually quite a large population of gamma ray bursts, that are probably ten times more common than the average gamma ray burst and that go undetected by the current gamma ray satellites, so the only way to actually study these events will be through optical, radio and x-ray wave bands, so as part of my PhD thesis I have a large survey where I actually monitor all supernovae in the nearby universe with the very larger radio antennae's to try to search for any evidence that they are also powered by gamma ray bursts, such as this event was. I think another interesting aspect is the idea of studying what sort of environments these explosions happen in and it's been found, actually, that gamma ray bursts actually occur in host galaxies that are very different from typical galaxies such as the Milky Way, so I think the next step would be moving towards understanding the connection between the galaxies of these events and the explosions themselves.

Chris Smith: Caltech's Alicia Soderberg and before that Germany's Paulo Mazzali, who both independently studied the energetics of the event XRF060218 – the second nearest gamma ray burst yet recorded. Now, whilst the link between gamma ray burst and supernovae has been well established, no one has yet observed what happens at the very beginning of a supernova and, therefore, the dimensions of the exploding star. But now, by studying the event we've just discussed, Sergio Campana and his colleagues from Brera Observatory in Milan were able to catch the dying star in the act of exploding. As it did so, the shock wave of the explosion stimulated the stars envelope, which is rather like a cocoon and this provoked the release of optical and ultraviolet signals and these signals gave the team the first opportunity to measure how large that dying star must have been. Nature 442, 1008–1010 (31 August 2006) , Nature 442, 992–994 (31 August 2006)

Sergio Campana: Each gamma ray burst is a peculiar supernova and, for the first time, we are looking at a star in the act of exploding and the gamma ray burst is the marker of the ongoing supernova. Normal stars like our sun lives their life and gently turns to white dwarfs at the end of their lives. Heavier stars die with big explosions that we call supernovae. During these explosions the star is completely disrupted and only a compact remnant like a neutron star, black hole remains. These supernovae are discovered usually ten to 20 days after this explosion because the remnant is energised by radioactive decays only after this time, so we can discover supernovae in external galaxies only days later. Our peculiar discovery is the fact that we observed the envelope of the star energised by the supernova explosion and this is the very first time that we observed a similar phenomenon.

Chris Smith: So what actually is the envelope of the star though, when you say the envelope do you mean just the outer portion of the star? Or is there some kind of gaseous enclosure around the star that you were looking at?

Sergio Campana: It is not clear because such massive stars lose a large part of their envelope during their life, so there is a lot of material from the star close to the star itself. So what we can say is that there is a lot of matter very close to the star. This led us to constrain the initial radius of the stars, which is a very important result because it is the first time that we can have a hint of the radius of... of a progenitor of a gamma ray burst and also of a massive star, which is more or less six times larger than our sun.

Chris Smith: And that value for the exploding star, at six times the mass of our own sun, fits nicely with Paulo Mazzali's and Alicia Soderberg's suggestions that x-ray flashes are the results of the deaths of smaller stars. Now finally this week, RNA interference, the technique of switching off genes by injecting small RNA molecules which are the mirror image of the genes own RNA. It could have enormous therapeutic potential. Only recently on the Nature podcast we heard how researches have used the technique to lower blood lipid levels in monkeys by switching off a gene that regulates cholesterol. But now Ronald Plasterk has found that it can also produce effects which are certainly not temporary. In fact he was able to show that the effects could last, quite literally, for generations. Nature 442, 882 (24 August 2006)

Ronald Plasterk: One of the very first things discovered about RNA interference, RNAi, when it was discovered by Craig Mellow and Andrew Fire was that is was inheritable. So what they would do is inject RNA into a worm and then in the next generation see that a gene got silenced, you know, it's activity was shut down and actually then noticed already, the first time they did the experiment, that it would inherit for one more generation. But worm generations are only two or three days so it could still be passive dilution of the silencing effect. And what we now found is that actually inheritance can be indefinite, so if you keep picking the progeny in which the gene is silenced, you could keep picking those for 80 animal generations. So, for a very long time.

Chris Smith: So what do you think is going on to make that happen?

Ronald Plasterk: Well, what we think, and also based on further genetic analysis, is that initially what you have is RNAi, so that means that double stranded RNA silences a gene by shutting off the activity of the transcript of the message RNA, but apparently the information goes to the nucleus and shuts off the gene there and one of the reasons for saying that is that we found that chromatin factors are required for the maintenance of the silencing effect.

Chris Smith: So, in other words, the silencing effect is having a second effect which is that you get a remodelling of the chromatin to make that gene switch on or switch off subsequently?

Ronald Plasterk: Precisely.

Chris Smith: Do you know how that's actually being achieved though?

Ronald Plasterk: No, we don't know about the mechanism, as I said we found four genes that you need for this silencing to be inheritable and they're all chromatin related factors, so that does suggest, indeed, that something happens there. We could, by analogy, think that it works the same as it works in fungi where something similar has been described. So it hadn't been seen in animals at all but it has been seen in single, unicellular fungi. We don't know at all if it is the same, but if it is then there must be something local happening at the DNA, at the chromatin, that also involves local RNA synthesis.

Chris Smith: So, given that worms are pretty easy to study, what did you do in order to arrive at the results that you did? What was the actual experiment?

Ronald Plasterk: Well, one of the first experiments was to silence a homeobox type gene and see that you got affected progeny and if you kept picking it's progeny then you kept seeing the effect over and over again. And then we actually tested a couple of hundred genes for which we knew RNA interference gave nice visible phenotypes in the worm, and for all those tried, if we silenced the gene and kept picking silenced individuals in the next generation, the effect would persist and we found that actually for over 20 of them we could find that, so it didn't seem something unique for one gene, it seemed a fairly general phenomenon. I would now think that it probably works, to some level, at every gene that is expressed in a germ line.

Chris Smith: There have been a couple of papers this is year, in Nature, in which individuals have begun to home in on the process of paramutation and an RNA dependent RNA polymerase, seems to play a key role in that, do you think that might be involved here?

Ronald Plasterk: It might well be. One of the questions we haven't answered, we're working on that right now, is if you have one locus which is silenced and you cross that in with a wildtype version of the gene which is not silenced, whether the effect will actually jump to the other allele, so in other words, when it can go from one chromosome to the other, we don't know that yet.

Chris Smith: Ronald Plasterk from the University of Utrecht, who's shown that, at least in the worm, the effects of RNA interference can be passed on for 80 generations, although we don't yet know how. Well that's it for this week and thanks for listening. Next time I shall be getting the low down on methane and getting to the bottom of a volcano. This week's show was produced by Anna Lacy and Derek Thorne and I'm Chris Smith. Until next time, goodbye.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.