Nature Podcast 22 June 2006

Introduction

This is a transcript of the 22 June 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

Chris Smith: Hello, and welcome to this week's edition of the Nature Podcast with me, Chris Smith. In this programme: why the San Andreas fault looks like an earthquake could be imminent at any time; researchers are getting to the bottom of the Piezo electric effect; we'll be probing the origins of a key part of the immune system, and also hearing how scientists are uncovering the causes of deafness. First, though, to cancers and what causes them. For a long time we've known that certain genetic mutations can predispose an individual to developing tumours in certain tissues, but who would have thought that the immune system could be responsible for triggering them. John Letterio from the Rainbow Babies and Children's Hospital at Case Western Reserve University in Ohio has studied a mouse model of one of these syndromes which causes tumours in the gastrointestinal tract. By selectively switching on a mutated gene in just the gut epithelium or in the immune T-cells sitting beneath the gut epithelium, he's pointed the finger firmly at the immune system as the cause of the cancer. Nature 441, 1015 (22 June 2006)

John Letterio: What we've discovered is that there's an important molecular basis that links the susceptibility between chronic inflammation in the gastrointestinal tract and cancer. We chose to focus on a disease where there was a known heritable mutation that had been described. This is the syndrome in which patients or families are predisposed to developing gastrointestinal cancer, and the prevailing view or wisdom has always been that you're born with a mutation in one allele of this gene, and then over time during your life you may mutate or silence or lose expression from the other normal copy of the gene, and ultimately the cells that line the intestinal tract become cancerous.

Chris Smith: So what's the relationship to inflammation here?

John Letterio: The reason this particular disease is interesting is that over the years, in patients that have been followed, with this syndrome, it's been observed that there's a smouldering inflammatory process that is always there, before they develop polyps or frank malignancy or cancers, and so this supposition that the underlying stroma, the cells that reside within the gastrointestinal tract underneath that overlying epithelia, may have a part to play in the development of the cancer. So what we decided to do in this case was, in a model of the disease, in a mouse, to target that particular mutation either to cells of the immune system, and in this case its T-lymphocytes, or to restrict the mutation to the epithelial cells, the cells that line the gut and actually then become the cancer cells.

Chris Smith: And what did you find when you did that?

John Letterio: It's interesting: we found that in the models where we restricted the mutation to the epithelial cells, the mice never developed cancer, but when we restricted the mutations only to the T-lymphocytes, in each case the animals developed spontaneous gastrointestinal tumours throughout the GI tract. And, in an interesting way, in the sense that the models recapitulate what we see in patients with this disease, there's a smouldering, underlying inflammatory process that ultimately is eventually associated with these carcinomas that develop in the GI tracts.

Chris Smith: So the inflammatory cells and the inflammatory process, essentially whipping along the epithelium at a higher rate of cell turnover than normal, is that what eventually discloses a carcinoma?

John Letterio: That's exactly right. In reality, what we're uncovering here is that there's a very intricate communication between cells of the immune system and cells that make up the gastrointestinal tract: these epithelial cells. For a long time we've thought that these lymphokines or cytokines that are made by various cells in the immune system are just really intended to provide a mechanism for communication between the cells of the immune system, but in fact, a lot of these epithelial cells in the gut have receptors for these cytokines. So they actually are affected by a lot of the factors that are produced during this chronic inflammatory process.

Chris Smith: Is there a way of interrupting the process so that you can stop that malignant transformation? Are there any particular factors that you can switch off?

John Letterio: That's exactly where this field needs to go, and I think that's why this observation is so exciting. What we need to do is really focus on the development of therapeutics that aim to turn off these immune responses. So in the case that we've described, the goal should be actually to look at therapeutics that somehow turn off these activated T-cells or interfere with the activity of the cytokines that they produced.

Chris Smith: John Letterio. And now to the San Andreas fault. It's 100 years this year since the great San Francisco earthquake which was triggered by a rupture of a 300 mile long section of the northern part of the fault. The effects were felt as far away as Oregon; thousands of people were left homeless and the damage at the time was estimated to be the equivalent of $500 million. But the southern part of the San Andreas fault didn't rupture, and it's continued to accumulate a so-called slip deficit ever since, and that now stands at some seven to ten metres. Yuri Fialko from the Scripps Institution of Oceanography is predicting an imminent shake-up. Nature 441, 968 (22 June 2006)

Yuri Fialko: We know that the greatest earthquakes in California occur in the San Andreas fault, a big plate boundary fault that separates the North American and Pacific plates. It's the king of fault faults in California, if you will. The two most recent great earthquakes ruptured the central and northern part of the fault 150 and 100 years ago, but the southern part of San Andreas has remained quiet for as long as historic records go, which is now more than 300 years. Naturally, we'd like to know whether this quiescent translates into a significant seismic hazard, especially given the proximity of southern San Andreas to large populated areas such as the cities of Riverside, Palm Springs, Santiago and Los Angeles.

Chris Smith: So what have you done to look into that?

Yuri Fialko: The questions about seismic risk can be addressed with precise measurements of deformation or displacements across the fault traced. In this study, I used data collected by several techniques including space-borne satellite interferometry or INSAR [Interferometric Synthetic Aperture Radar] for short, and the global positioning system.

Chris Smith: So what are they actually physically measuring on the ground? Are there literally markers on the grounds that are moving relative to each other?

Yuri Fialko: That's right. INSAR satellites are equipped with a powerful radar that illuminates their surface with microwaves and measures the reflection. By combining the reflections collected at different times, we're able to detect various small, down to a millimetre scale, motions of the Earth's surface that occurred between the satellite passes. I looked at the number of radar images from Southern California and what I saw was a very subtle but unmistakable pattern of what we call inter-seismic deformation around the fault.

Chris Smith: So what does that actually mean in physical terms?

Yuri Fialko: The deformation that we observed basically shows how the Pacific and North American plates move past each other, but, more importantly, these new data tell us precisely how that motion is accommodated and partitioned between measured faults in the area. For example, we found that the southern San Andreas accounts for about one half of the relative plate motion, and it moves at a speed up to about one inch per year. Another active fault is the San Jacinto fault to the west which moves almost as fast as San Andreas, and in fact quite a bit faster than previously believed.

Chris Smith: So why is there a difference between what the northern part of the fault and the southern part of the fault in California are up to?

Yuri Fialko: We know that the northern part of the fault has ruptured and the great San Francisco earthquake, the centennial of which was commemorated this year, but the surprising part of the southern San Andreas is that it hasn't produced a large earthquake as long as historic records go, which is more than 300 years. One hypothesis is that it's currently primed for another big earthquake, and in fact our new data confirmed that hypothesis.

Chris Smith: Does it give you any clue as to when that might be, apart from saying it looks like this is primed to go off but we don't know when?

Yuri Fialko: That's right. We cannot tell precisely when that next big event will occur. It can be tomorrow or it could be 20 years from now. However, it appears unlikely that the fault can take another few hundred years of slow loading and straining.

Chris Smith: More than just a concerned resident, Yuri Fialko from the Scripps Institution of Oceanography in Santiago, California with worrying findings from the southern San Andreas fault.

Nature's Podcast, bringing the world of nature to life. Coming up shortly, the origins of the Piezo Electric Effect, where the thymus comes from, and why deaf birds but not humans can regain their hearing. First though, with news of brain scans designed to weed our liars and concerns about the future of bio banking, talking with Anna Lacey, here's Nature's Jim Giles.

Jim Giles: Thanks. So we've got three stories this week and the first of them takes us to Spitsburg which is a small island owned by Norway close to the North Pole, and it's in this tough, cold environment that an organisation called the Global Crop Diversity Trust is attempting to set up a seed bank. They're calling it a kind of Doomsday seed bank. What it's going to do is essentially provide a very safe place to store varieties of the world's food crops, seeds from those crops, so in the event of a severe drought, a climate change, or even something like a nuclear war, where a particular species of crop was eradicated, people will be able to call on these stores here and hopefully revive that species.

Anna Lacey: But why Norway?

Jim Giles: Well, the island's got a lot going for it for this kind of facility. It's free of earthquake activity. It's also extremely cold; the temperatures, which average around -4°, probably preserve the seeds. But, to be extra sure, the Trust is using coal from a local mine to power refrigeration units and to cool the facility to around -20 to -30°

Anna Lacey: So what, are they just going to be putting it down in the ice, or how will this seed bank be built?

Jim Giles: Essentially, it's going to be excavated from a sandstone rock and it'll consist of a long tunnel which will take people into a storage facility, and the seeds there will be wrapped in aluminium foil to keep out moisture, and the whole facility, which won't even be manned because it is so remote, will be protected by a couple of doors and motion detectors to make sure that no one can get in or out without approval.

Anna Lacey: But what about if something does happen to this Norway seed bank? Then what are we going to do?

Jim Giles: Well, if something happens to this seed bank, it could potentially be quite bad because the whole point of this bank is to provide a backup. There are several seed banks that already exist, and they're really designed to protect very important food crops; the problem is that these banks have for many years now suffered from a lack of funding. Some of them are in very bad condition, and the future of many of them is uncertain, so what the Trust is trying to do is to provide a backup to all of those banks so that if something goes wrong there there's a kind of fallback position.

Anna Lacey: It's not just seeds this week that are being stored, ready for the future, there's also another story about tissue banks.

Jim Giles: Yes. Tissue banks or bio banks are really quite a big thing in biomedical research at the moment. The idea is that you get together tens or hundreds of thousands of samples from people and you match them to personal health records. The idea is that if you get enough samples and match them to enough health records, you're able to tease out the genetic and environmental causes which lie behind diseases like Alzheimer's, for example. Now, several bio banks have been set up: there's one in the United Kingdom; Iceland has one that's already up and running; Estonia is planning a very large one, and there are slightly smaller initiatives underway in the US, but those have been hit by a scandal involving a neuroscientist named Trey Sunderland who, last week, was revealed to have earned almost $300,000 by sending about 3,000 samples of spinal fluid to the drug company, Pfizer, without approval from his employers, the National Institute of Health.

Anna Lacey: There have been scandals in the past where people have gone and sold organs, for example. Might this kind of scandal be deterring people from donating tissue in the future?

Jim Giles: Well, that's the big fear. I mean, in the UK there was a scandal a few years ago at a hospital in Liverpool where a pathologist was revealed to have stripped the organs from bodies of children on which he conducted post-mortems and what the pathologist noticed after this was revealed is that there was a drop off in relatives who were willing to have the organs of their dead relatives donated. Now, if there is a possibility that a tissue sample you donate could be sold or could be used for something that you haven't permitted it to be used for, that's obviously a massive disincentive to donors.

Anna Lacey: Well, all might not be lost because it seems that dodgy deals like this might actually be uncovered by a new development in lie detection.

Jim Giles: They might be but that would be pretty controversial. This is the story about two American companies; one's called No Lie MRI and the other's called Cephos who are both about to launch, later this year, commercial lie detection systems based on magnetic resonance imaging. They use brain scanning technology which can essentially look into the areas of people's brains which we know to be possibly more active when people tell lies, and that can be used, in theory, to provide more accurate lie detection systems.

Anna Lacey: So how did they actually test this?

Jim Giles: This is based on quite a long history of research. For example, in one experiment, subjects were given five playing cards and a $20 note and they were told that they could keep the money if they could conceal which card they'd hidden the money under, and they scanned their brain while they were telling these lines, and then they've looked for the bit of the brain which lights up during a lie. Now, one of the big problems is the incentive to lie to earn $20 is quite minor compared with the incentive to lie, for example, to conceal involvement in a terrorist plot, so many neuroscientists were asking whether we can be sure, without a lot more research, whether these scans can reliably detect deceit across all these different situations. If you scan lots of people, you do find that there are certain areas of the prefrontal cortex at the front of our brain which are more active than normal when people lie. That's not the same, of course, as being able to put an individual in a scanner and being able to reliably say whether they're lying or not when they are actually lying. So the use of an MRI scan on an individual is much more controversial.

Anna Lacey: But with the science aside here, ethicists must be up in arms about this.

Jim Giles: Oh, yes. I mean, this is a fascinating case because, of course, no one at the moment can be forced to undergo one of these tests, but you could foresee a situation where an insurance company could say, every time you submit a claim to us we'd like you to go and take one of these tests. So it does concern ethicists that before the arguments have been properly talked through, these technologies are coming on to the marketplace.

Chris Smith: Anna Lacey catching up on some of this week's other science news, including the MR Lie scan with Nature's Jim Giles.This is Nature's Podcast in the 22nd June edition of Nature with me, Chris Smith. If you'd like to find out more about any of the reports we're discussing, they're all available on our website at http://www.nature.com/nature. There's also a text transcript that'll accompany this show which is available at http://www.nature.com/podcast. If you'd like to send us any feedback, drop a line to Podcast at http://www.nature.com. Now, to the Piezo electric effect: the way certain materials alter their shapes when an electric current is applied to them, and vice versa. But why does this occur? Robert Blinc is from the Josef Stefan Institute in Ljubljana, Slovenia. Nature 441, 956 (22 June 2006)

Robert Blinc: Piezo electric systems and relaxors convert electrical energy to mechanical work. In some of the systems, there is a giant electro mechanical response which is very important for robotics, for medical imaging, for ultrasonic transmission, sonars and so on. In medical imaging, ultrasonic medical imaging, you get a ten times or hundred times better resolution in the pictures. The reason for this giant effect was not known until now.

Chris Smith: So, in other words, when you say giant effect, for a small amount of electricity you get a very big movement?

Robert Blinc: Yes. We get a very large electro mechanical response.

Chris Smith: How did you go about trying to dissect what was happening?

Robert Blinc: We discovered a critical point. Perhaps I can say that everybody knows the critical point in water. Water becomes steam at 100° at normal pressure, but if you go to higher pressures, let's say 22 megapascals, there is no difference between steam and water. It's the same phase. So this is a highly unusual situation, how water behaves. And we discovered the same effect in relaxors, this highly unusual level. Nobody saw it before in this type of system. And water flows but relaxors are solid, therefore you have a tremendous strain and with a very small electric field you can produce large mechanical formations. That is the whole point.

Chris Smith: If you could zoom in with a really powerful microscope, what would you see going on inside the material to produce these displacements that you see?

Robert Blinc: The ions in the solids are usually very fixed in a certain position; as they define the polarisation, they give direction. But if you want to move the ions from one equivalent position to another, you have to apply a large electric field and use a lot of energy. This is the so-called polarisation rotation which is basic for the Piezo effect, and this gives a mechanical formation. But near the critical point, the ions in a way become very lose. They seem to flow in the solid and you can move them with very small fields from one position to the other, and it costs practically no energy. The ions would move like, I would say, a kind of super-fluid in the solid.

Chris Smith: Do you think it's going to be possible now, with this in mind, to come up with materials that are even better?

Robert Blinc: I'm sure of that. We have already seen two other types of materials where the same effect takes place, and we are pretty sure that this is a very general phenomenon.

Chris Smith: Robert Blinc. Now, from the origins of the Piezo electric effect to the origins of the thymus, the structure that orchestrates the development of T-lymphocytes: the cells that help to power our immune systems. Critically, there are two layers to the thymus: an outer rind or cortex, and an inner medulla. How these two layers came to be no one knew, but now the problem has been solved. Teeing off from Birmingham University in the UK, here's Graham Anderson. Nature 441, 988 (22 June 2006)

Graham Anderson: What we've discovered is a cell in the thymus that is able to give rise to the two major epithelial components of the thymus, so the thymus is a very specialised organ which is in the chest, just lying above the heart, and so far it's known that it's got one very, very important function and that is it's the place that T-cells develop. And in the absence of a thymus, any individual organism lacks T-cells, so the thymus is a very important organ in terms of the immune system because it's T-cells are the cells that fight viral infections.

Chris Smith: And there are two components to it.

Graham Anderson: Yes. It's like a lot of other organs in that it has a cortical region and a medullary region, and different events occur in the cortexes compared to the medulla. For example, in the cortex, developing T-cells receives signals for differentiation, whereas in the medulla, developing T-cells receive signals which prevent them from being auto reactive and chewing up your own body tissues.

Chris Smith: Given that they've got functional differences, do they also have different developmental origins then?

Graham Anderson: Well, this was the question that's been unclear for many years. Because there are two distinct areas of the thymus, it was unclear whether both share a common origin or whether they come from distinct cellular components in development.

Chris Smith: What did you find?

Graham Anderson: What we found was that both components share a common origin, and this is these bi-potent progenitors that we found that are able to give both cortical and medullary epithelial cells.

Chris Smith: Where do these cells come from in the first place?

Graham Anderson: Traditionally, it's been thought that the epithelium in the thymus comes from either exiderm and/or endoderm, and so these are gerboles [?] that are present in the early embryo. Some supporting evidence has suggested quite recently that endoderm was the source of all fine [?] epithelial cells, but it wasn't clear whether there was heterogeneity in the endoderm that gave rise to cortical epithelium, and medullary epithelium.

Chris Smith: How did you prove that it wasn't anything to do with that?

Graham Anderson: We just took a single cell from an early thymus rudiment and it happened that this thymus rudiment was from a mouse that was expressing yellow fluorescent protein, so this was just an indelible marker to try and trace that cell and the progeny of that cell. We introduced that single cell into a foster thymus of the same age, so essentially we were taking one cell that we could follow and putting it back into a thymus that was age matched, thinking that maybe that sort of thymus would provide all the necessary signals to reveal its potential. Then we grafted that thymus under the kidney capsule of the recipient mouse to let it grow up and develop normally, and then just simply looked to see which cells were carrying this YFP indelible marker.

Chris Smith: So you've got a progenitor that can produce cells that can turn into both things, but surely the key question now must be, what drives them to make those decisions.

Graham Anderson: That's right. I think that's a very important point: the mechanism of lineage choice now. I think also, another important point is to know how long these cells persist in the thymus, because in our study we were able to show that these were present in the early thymus, in order to get the thymus to develop in the first place. But what will be very nice to know is that these cells maybe exist in the postnatal and adult thymus.

Chris Smith: If you can work out how this actually is orchestrated, do you think there's the potential to recreate a thymus and therefore re-educate people's T-cells if they've got autoimmune diseases, for example?

Graham Anderson: That's right. I think it's a long way down the line, but I think it's the first step in trying to understand how we can kind of play around with thymus function, thymus growth.

Chris Smith: Birmingham University's Graham Anderson. And, as Graham pointed out to me, if we can work out how to recreate a thymus, it might be possible to rescue the damaged immune systems of people with immune-disabling disorders such as HIV. Now, another person who's been looking at how we develop is Neil Segil from the House Ear Institute in Los Angeles. He's trying to find out how the inner ear's hair cells, which turn vibrations into neural signals we can understand, can be regenerated from nearby supporting cells. But first he had to come up with a way to pinpoint these cells in the dish. Nature 441, 984 (22 June 2006)

Neil Segil: We've done a very simple experiment that has required a lot of technical build-up; the simple experiment was to test whether a particular cell in the inner ear has the capacity to begin to divide again and regenerate a class of cells known as sensory hair cells, which are very frequently lost, and their loss is a major cause of hearing loss in the world.

Chris Smith: Because in some animals they can be replaced, can't they?

Neil Segil: Yes. In many vertebrates, except for mammals, those cells, when they're lost, can regenerate. In birds, for instance, that are deafened, they have full functional recovery in a matter of a couple of weeks. However, in mammals like mice and humans, when those cells are lost, and they're extremely sensitive to all kinds of environmental trauma like noise and many kinds of antibiotics, they're gone for good. We don't know why regeneration doesn't occur, and, as you pointed out a moment ago, in other vertebrates those cells can regenerate and they do so by the supporting cells that surround each of the sensory hair cells beginning to divide and then trans-differentiating into hair cells.

Chris Smith: So what did you do to try and dissect what's going on here?

Neil Segil: The first step was to develop means to accurately identify those cells once we had removed them from the inner ear, so we developed a transgenic mouse that has a green fluorescent protein expressed under the control of a gene that's expressed in these supporting cells. The second step was indeed the purification, and that's a bit harsh. We have to dissociate the entire sensory epithelium into single cells and put it through a machine called the fluorescent activated cell sorter, and then collect all of the green fluorescent cells, which are the supporting cells. The third step was to develop the tissue culture method, the in-vitro method that allows these cells to show us their capacity to do this.

Chris Smith: Now he can identify the supporting cells, Neil and his team have begun to look at their ability to turn themselves into new hair cells. By comparing supporting cells from new-born and two-week-old mice, it looks like there're actually two components to the challenge of regenerating new hair cells.

Neil Segil: There is a dramatic change between the new-borns and the two-week-olds. In the new-borns, a large percentage of those supporting cells can begin to divide and then trans-differentiate into hair cells. Two weeks later, very few of those cells can begin to divide, and yet many of those cells can still differentiate into hair cells. That tells us that the regulation of this ability to re-enter the cell cycle is separable, in some ways, from the ability to transform into hair cells. So it breaks down into two problems now: one is how you control cell division, and the other is how you control the trans-differentiation.

Chris Smith: Neil Segil from the House Ear Institute in Los Angeles. In his honour, perhaps, it should be re-named the Mouse Ear institute. Well, that's it for this week, and thank you very much for listening. Before I go, let me just tell you about a new online resource which has recently been launched. It's Nature's news blog which provides a digest of scientific news stories and enables you to then comment on them. You can also comment, for instance, on this Podcast, which is listed there. To find the Nature news blog, you just need to point your web browser at http://www.nature.com/blogs. Next week we'll be looking at the science of germanium, but in the meantime, for those of you with an interest in all things creepy crawly, this week's edition of the Naked Scientist Podcast looks at the science of insects, including how locusts might hold the key to making the roads safer in future. That's because they have the neurological equivalent of an anti-crash system. That's the Naked Scientist Podcast which is freely available from http://www.thenakedscientist.com. The Nature Podcast is produced by Anna Lacey and Derek Thorne and I'm Chris Smith. Until next week, good bye.