Nature Podcast 27 April 2006
Introduction
This is a transcript of the 27 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.
Advertisement: The Nature Podcast sponsored by Bio-Rad. Transform your 2-D electrophoresis sample preparation with Bio-Rad's new MicroRotofor cell. On the web at http://www.Discover.Bio-Rad.com.
Chris Smith: This week, a new way to tackle heart attacks and strokes, we'll be finding out why Uranus is spinning off kilter, why songbirds have a distinctly human nature to their tunes, how tree rings in Pakistan are telling a tale of climate change and the origins of fish gills and jaws. Hello, I'm Chris Smith and welcome to the Nature Podcast from the 27th April edition of Nature. Now roughly one in three of us is destined to die from heart disease, which makes this first story very welcome news. Mark Pepys from University College London and his colleagues have made a drug that can block the action of CRP or C-reactive peptide which all of us carry in the bloodstream and which can amplify the damage of a heart attack or stroke. By blocking it, though, you can cut down that damage. (Nature 440, 1217–1221; 27 April 2006).
Mark Pepys: What we've done in this work is to design and synthesize a complexly new compound as a drug to antagonize the harmful effects of a protein that everybody has in their blood, called C-reactive protein. This protein almost certainly increases the amount of damage when people have heart attacks or strokes and our paper reports the design, the synthesis and the efficacy of this new potential drug compound.
Chris Smith: How have you gone about designing that drug?
Mark Pepys: Well, we know a great deal about the structure and the properties of our target protein, C-reactive protein, so I sat down with a piece of paper, and together with my crystallographic colleagues, we wrote down the formula of what we thought should be the drug and then we engaged out chemistry collaborators who synthesised this new molecule. We then went on to look in experimental model systems, where one causes injury in the heart and we showed that giving C-reactive protein increases the injury and giving the drug plus the C-reactive protein reduces the injury back down again. The bottom line is that it works.
Chris Smith: How does CRP cause its toxic effects?
Mark Pepys: Well, it causes damage to tissue by binding to cells which have already been injured or which are dead as a result, for example, of the blockage of the blood supply that causes a heart attack and after it binds to these targets it activates a system in the blood called compliment, which is a complex cascade of proteins and that, in turn, damages more cells and more tissue than would be damaged by the original insult.
Chris Smith: So your agent gets in the way of that cascade becoming active, does it?
Mark Pepys: Exactly, what our compound does is it prevents the initial step which is the C-reactive protein binding to damaged or dead cells. And if the CRP can't bind to those targets then it doesn't activate the inflammatory system which causes the extra damage.
Chris Smith: This is in animals?
Mark Pepys: Yes.
Chris Smith: So do you think this is going to work in humans? Will there be any interactions that you can't account for, that it might not work?
Mark Pepys: Well, there are always unknowns when you take a new drug molecule into humans for the first time, but so far this molecule looks exceptionally safe. It's exceptionally specific; it is not bound by anything except C-reactive protein. We have no reason to believe that blocking C-reactive protein for a few days, which is all we would need in the heart attack or stroke situation, would do any harm, so there no a priori reasons for worrying about whether it's going to have toxicity but, clearly, we will proceed cautiously when we come to that stage, just as everybody does when they do those sorts of tests.
Chris Smith: There is some evidence, isn't there, that people who have raised levels of CRP during their life, are more prone to developing arterial disease. So does that mean, then, that if you were able to chronically dose people with this agent, you could potentially stave off heart attacks and strokes?
Mark Pepys: Well, that's an excellent question and I'm glad you asked it because, in fact, it was our own observations which started off the recognition of the association between raised C-reactive protein and future risk of heart attack. But, unfortunately, people have tended to exaggerate the importance of that association. The evidence is not strong that CRP has got anything to do with the pathogenesis of the processes that lead to heart attack. What is robust is that, once you have a heart attack, and tissue is dying as a result of lack of blood supply, that then the presence of CRP makes the damage worse than it would otherwise be and blocking it in that acute time, just when the patient comes into hospital, could be beneficial.
Chris Smith: Are there any other conditions that this might prove very useful in treating, apart from heart attacks and strokes?
Mark Pepys: Absolutely, CRP is a very non-specific marker of virtually all sorts of inflammation and tissue damage that almost anything which make a person sick trigger increases in C-reactive protein, so there's every reason to believe blocking it might be a good thing to do. In the future we hope that if this drug and better drugs might well be very useful adjuncts to treatment in rheumatoid arthritis, in inflammatory bowel disease, in various infections, in all situation where you've got damaged tissue in the body and the body responds by making a lot of CRP, I believe the CRP could be making things worse than they would otherwise be and, therefore, a drug like this could be helpful.
Chris Smith: Mark Pepys, from University College, London with a new drug that might help to cut down the damage done by heart attacks, strokes and, possibly, any form of inflammatory condition. Next up space, and an elegant model to explain why some of the planets in our solar system seem to be spinning off kilter, like Uranus, for instance, which almost looks like it's tipped over 90° sideways. No one knew the answer as to why this was the case, but some people speculated that it could have been down to cosmic collisions that were taking place in the early days of the solar system, but now we think we know the answer. Adrian Brunini from Argentina's Universidad Nacional de La Plata has built a computer simulation that shows that resonances, in other words, gravitational interactions between the planets, as they assumed their final positions, are probably responsible. Here's Nature's Lesley Sage. (Nature 440, 1163–1165; 27 April 2006).
Lesley Sage: What Adrian Brunini has found is an explanation for the orbital inclinations of the giant planets, he's found that if they migrated through what's called a resonance, where Jupiter goes around the sun twice for every one orbit of Saturn, the gravitational interactions between those four planets would explain the way the solar system looks now. It gives Jupiter a small, but measurable inclination, Saturn a much larger one and almost all of the simulations tend to turn Uranus on its side.
Chris Smith: Now one thing that people have suggested in the past is that the reason that Uranus has this rather strange rotation is because it perhaps had a collision with something else, is Adrian Brunini discounting that theory then?
Lesley Sage: It isn't that he's really discounting it, the problem is that you have to have a pretty big object hit a planet as big as Uranus to turn it on it's side and where's that going to come from? Because the motion of the bodies in the early solar system was basically in a plane. So you could have things going around the sun, what we call prograde rotation or you could have some that were going retrograde, backwards, but in order to turn Uranus on its side, you're going to have to have something coming, basically, out of the plane of the solar system and, as far as we know, that's fairly unlikely.
Chris Smith: Now, if you look at the satellites that these individual inclined planets have, are they also wobbling, have they tipped over too? Which would be consistent with this idea?
Lesley sage: Yes, they are. And that's another one of the advantages of this model, that the regular satellites, the ones that we think formed along with the planet, are tilted with the same inclination as the planet itself.
Chris Smith: And how did Brunini actually arrive at these conclusions, what was his experimental method?
Lesley sage: Well, he was using numerical integrations, so it was a computer model, but what makes this interesting is that it has explained all four of the giant planets all at once, there's no loose ends to tie up, no piecemeal, well you know Saturn did this and Uranus did that, and Neptune did something different, it's just a nice clean package and it all hangs together.
Chris Smith: That's bound to strike a chord with a few people, Lesley Sage commenting on Adrian Brunini's resonances model of why some of the planets in the solar system appear to have tipped over. Coming up shortly we will be hearing how starlings are the darlings of the birdsong research world, how tree rings are telling researchers about rainfall 1,200 years ago and another piece in the fossil puzzle of where we get our jaws from. But first, with a look at some of this week's other major science news stories, and talking to Anna Lacey, here's Nature's Jo Marchant.
Jo Marchant: Thanks, I'm gong to talk about three new stories this week, the first one is about vaccines against bird flu. The main problem facing manufacturers at the moment is simply that there's gong to be a pretty big gap between how much vaccine they would actually be able to make in the event of a bird flue pandemic and then how much vaccine we would need. Neil Ferguson at Imperial College, London and his colleagues, found that to kerb the spread of the disease you need to start vaccinating people within one to two months of the pandemic starting, but at the moment the best case scenario is that we'd be able to make enough vaccine to protect around a billion people throughout the world, but only one year after a pandemic emerges. (Nature 440, 1099; 27 April 2006).
Anna Lacey: So, what are they suggesting?
Jo Marchant: Well, there's a few different strategies that companies are trying and what we're focussing on this week is the idea of using whole-virus vaccines, these were used back in the 1960s for flu vaccines but they do tend to trigger side effects such as fever and pain. So most companies ended up switching to split-virus vaccine, where you're actually breaking the virus apart, but you need higher dosage, so what some experts are saying now is that, with the threat of the pandemic, where we know that we may not have enough vaccine to go around, we should perhaps look again at these whole-virus vaccines.
Anna Lacey: But how long are these new whole vaccines going to take to develop?
Jo Marchant: Well, it's difficult, I mean the experts that kind of favour this approach are saying that this could be a quicker path to having a greater vaccine supply because, you know, straight away you've got a vaccine that can be used at much lower dosage. The difficulty is that they still have to go through clinical trials, a lot of the pharmaceutical companies are set up for making split-virus vaccine, so they are kind of saying well, yes in theory whole-virus vaccine should be great, but in terms of actually trying to make a vaccine quickly the priority is just to use the equipment that we've got, use the techniques that we are already using and make the split-virus vaccine, so there's a bit of a debate there over which is the best way to go.
Anna Lacey: Well, let's move now to another debate that's been fuelled by some new fossils found in Ethiopia. (Nature 440, 1100–1101; 27 April 2006).
Jo Marchant: Yeah and this has been triggered by a paper that was in Nature a couple of weeks ago, looking at hominid evolution during a period of around 4.4 million years ago to around 2.9 million years ago. So we're looking at Australopithecus and Ardipithecus. What everybody is trying to work out is, did basically one evolve into the next in a nice clean, direct lineage, therefore all of these species are pretty much our ancestors directly or do they just represent different branches of the hominid family tree? For this particular time period, Tim White and his colleges, who are the author of this new paper, think that they've got pretty strong evidence of the fact that Ardipithecus ramidus and Australopithecus afarensis and a species in-between, Australopithecus anamensis, evolved one into the other. The reason for that is that for the first time they found specimens of those three species pretty much in the same place but they don't see them overlapping, they don't see them existing at the same time.
Anna Lacey: So the people who don't agree it is one lineage, what kind of evidence would they want?
Jo Marchant: Well, if we found evidence of these species, sort of, overlapping and living at the same time or even, ideally, if you had DNA evidence that would tell you one way or the other, but people who are more in favour of a kind of bushy tree picture of human evolution, basically are saying well, yes this is good evidence but you cant really make that conclusion because you just never know, you could find more fossils, more species but, almost, no matter how much evidence you have you can never prove it because you could always find more fossils and I think that's the fundamental point where the two camps, and it's almost a philosophical difference in belief, rather than anything that new evidence could sort out.
Anna Lacey: Well, there's even more science controversy going on this week, but this time it's among the physicists? (Nature 440, 1094–1095; 27 April 2006).
Jo Marchant: Yeah, that's right, a really interesting story, a paper that came out in Physical Review Letters last week, looking at one of the fundamental constants of physics, the mass of the proton compared to the mass of the electron. Protons are about 1,836 times heavier than electrons and that ratio is something that has been thought of, as just a constant in physics. Now we've got a paper coming out suggesting that perhaps that number is changing.
Anna Lacey: How are they measuring this ratio?
Jo Marchant: Well they are looking at how a gas of hydrogen molecules absorbs ultraviolet laser light. They had a cloud, a cool gas of hydrogen in their lab and the exact frequency of light that's absorbed by each hydrogen molecule depends on the relative masses of those particles, they've done this in their lab, basically to look at what that ratio is today, but then they've compared that with light from two very distant quasars that are shining through clouds of hydrogen around 12 billion light years away, so that's effectively giving you a number, for 12 billion years ago.
Anna Lacey: But how can you accurately compare the measurement here on earth with one 12 billion light years away?
Jo Marchant: Yeah, it's an amazing achievement isn't it? The main secret of their success was the laser that they built, so they were using data from the quasars that's already been published quite recently and then they've built their own ultraviolet laser in the lab that's especially designed for this very purpose and that is what gave them lab data 100s of times more accurate than any lab measurement before. I mean they reckon the number has changed by 0.002% over those 12 billion years. But they're not saying it's definite, they reckon there's a 0.3% chance that it could be, you know, experimental error or down to chance rather than this effect.
Anna Lacey: This is really shaking the foundations of physics, I mean, what is this going to mean if they really are changing?
Jo Marchant: That's quite controversial. What it would mean...what's clear is that its not explained by anything in physicists' standard models so it would take new physics to explain it. In terms of the proton/electron mass ratio it seems unlikely that protons are just getting lighter, it's probably going to be something more fundamental than that. One possibility is that various versions of string theory, these theories involve tiny extra dimensions, if a particle occupies all of these different dimensions, if those dimensions change that could affect property such as the matter of the particle. So this could be evidence of a string theory, so people are starting to get much more interested in the idea that these constants might be changing because it might give us a way into testing whether those theories are true.
Chris Smith: Anna Lacey catching up on the latest science news with Nature's Jo Marchant. All the stories we are covering this week are available on our website, at http://www.nature.com/nature and this podcast is also available as a text transcript, you just need to visit http://www.nature.com/podcast and then follow the text link next to the show you want to read about and if you want to write to us the email address is mailto:podcast@nature.com. And now starlings and how their song singing abilities are helping to shed light on how humans process language. Here's the University of California, San Diego's Tim Gentner. (Nature 440, 1204–1207; 27 April 2006 ).
Tim Gentner: In order to understand the way that human languages are patterned, you have to appreciate the way that humans can form novel sentences and one of the things that we do is continually make sentences longer and longer by embedding words or phrases into the middle of them, we're not so much concerned with how that is achieved as we are with the extent to which the ability to comprehend those sorts of patterns is shared with other organisms. And it turns out that songbirds are an excellent model system to do that in. What we show now is that in fact, songbirds are capable of learning to comprehend these sorts of, so called, recursive centre imbedded patterning rules.
Chris Smith: So what did you do, get these birds into the lab and then persuade them to learn a song and then get them to repeat it?
Tim Gentner: Well, we took all of the naturally recorded vocalisations of a single male starling and extracted eight snippets of acoustic signals that are called warbles and eight different acoustic patterns called rattles. And then we had two different patterning rules, either warble, warble, rattle, rattle or the pattern could go warble, rattle, warble, rattle and for simplicity I'll just call those now AABB or ABAB patterns. So every time a bird heard an AADD pattern it's task was to peck a button and overtime it heard an ADAD pattern its task was to do nothing. And if it was correct then we gave it a little bit of food.
Chris Smith: And then how did you vary the task?
Tim Gentner: Well, in order to demonstrate with any strength that they've actually learnt these patterns, we need to be able to show, not only can they recognise novel instances, but they also should be able to extend these patterning rules to even long and longer strings. So we asked birds if you know AADD, can you accurately recognise AAADDD or ADADAD and the answer to that question is yes.
Chris Smith: But why do birds need to be able to do this?
Tim Gentner: Well, that's a very interesting question. It doesn't appear to be the case that they are using this to vary the meaning in their song and it doesn't appear to be the case that this has any particular value for them. And that raises a number of interesting questions, one of which is how computationally expensive might this be? It turns out if you want to construct the machine that can learn these sorts of patterns all you need is one that knows about certain sets of A's and B's and some memory for A's and D's that occurred previously in time. And many, many songbirds have incredibly memories for their songs and their songs are organised into small units. So it might be that this sort of ability kind of comes along for free any time you have an organism that has some vested interest in remembering the units that comprise those signals.
Chris Smith: Warbles and rattles, it sounds like something an opera singer with bronchitis would produce, but that was the University of California, San Diego's Tim Gentner exploring the auditory skills of starlings. And to that favourite roosting place for birds and that's trees. Kerstin Treydte from the Federal Research Institute for Forest, Snow and Landscape Research in Switzerland has been looking at what oxygen-18 locked away in old tree rings can tell her about the rain and snowfall at high altitudes in Pakistan, over the last 1,200 years. Rather worryingly her results show that the 20th century looks set to have been the wettest in a millennium for Northern Pakistan. (Nature 440, 1179–1182; 27 April 2006 ).
Kerstin Treydte: We produced the first annually resolved millennium long oxygen isotope records from tree rings at about 4,000 metrrs above sea level and we investigated the oxygen isotope ratio of these trees and produced a record going back to 828 AD and with this record we found an extraordinary increase in precipitation in the 19th and 20th century.
Chris Smith: How does that oxygen-isotope-ratio change and how is that reflected in the tree? Why do they get different oxygen isotopes?
Kerstin Treydte: Well the tree takes up the water over the roots and this water has a typical isotope pattern. Now what we find in the tree rings is more or less this isotope pattern and this gives information about the source of the water. We found that this water is mainly snowmelt because, in comparison to rain, it's depleted due to its different temperature.
Chris Smith: You've only looked at one region in Pakistan, though, how generalisable do you think these results are?
Kerstin Treydte: You have take into account that the precipitation is a rather complex and local pattern, it's not a large-scale phenomenon itself. So on higher frequencies we do not assume that there are similarities but at centennial scales it seems that these patterns are comparable over climatologically different regions.
Chris Smith: Are there any old enough trees to go back any further or do you think about 1,200 years is going to be the limit?
Kerstin Treydte: Yes, this is a general problem that we need old trees, but there are other possibilities, we could use wood from old houses to go back in time or fossil wood from lakes, so we just need to extend our chronology spec and time using dead wood also, and this is possible, so also there are not really old trees growing in the climatological interesting regions, we can extend our records back in time.
Chris Smith: And what else to you need to look at here, what's the outstanding questions?
Kerstin Treydte: What we did here was a regional study, so what we need it a much more highly resolved global network of precipitation reconstructions. And this is what we are now working on in Europe for example so we need to know how representative this finding of this special climatological region is for other regions.
Chris Smith: Kerstin Treydte from the Swiss Federal Research Institute using oxygen-18 locked away in tree rings to work out how wet Northern Pakistan has been over the last 1,200 years. Finally this week we find out how fish came by their gills and jaws. This is a long standing question because gill structures don't preserve well as fossils because they are made of soft tissue, but Philippe Janvier from the CNRS in Paris, together with his colleagues from Quebec has found a specimen of a jawless fish called Endeiolepis which dates from about 370 million years ago. The gills are remarkably well preserved and they're contained in a long series of pouches, which would have pumped water along just like those seen in the Lampreys which are also jawless and swimming around today. (Nature 440, 1183–1185; 27 April 2006 ).
Philippe Janvier: What we have found is fossil fish called Endeiolepis in which the gills are exceptionally well preserved and prove to be enclosed in pouches, exactly like in Lampreys. We didn't know whether the pouched gills of Lampreys are ancestral or if it was a specialisation, but since we know that this fossil fish we discovered is more closely related to jawed fishes than to Lampreys, it shows that the pouched gills are primitive relative to the gills of most of the modern fishes.
Chris Smith: But why does this one stand out as so unusual? I mean, I know it gives you insights into the gill evolution, but what else about it makes it stand out?
Philippe Janvier: Well, this has that gills started as enclosed in pouches and then became relatively free, as in the Salmon, the transition which may have been relatively sudden, relatively rapid, is a very important anatomical revolution in the structure of the vertebrate head, as the ventilation in that way implies the existence of jaws, so without loosing our gill pouches or the gill pouches of our ancestors, we would not have jaws.
Chris Smith: It's a pretty radical change isn't it? How do you think they suddenly managed to come by it?
Philippe Janvier: We have no idea. Certainly the loss of the pouches that surround the gills in, for instance Lampreys, was a dramatic anatomical event, but fishes needed these pouches to suck in and out the water which ventilated the gills but when these disappeared they really needed to have a big water intake device which is simply the mouth and it had to move. So that's why the jaws were suddenly very important.
Chris Smith: So do you think Lampreys have regained this structure, or do you think they never lost it in the first place?
Philippe Janvier: No, they never lost it and they are extremely primitive, in fact there are two small groups of jawless fishes which still survive. All other jawless fishes which were rather numerous in the Devonian period, have disappeared.
Chris Smith: So what do you think enabled them to survive, why are they so successful and everything else eschewed these particular structures and went for jaws?
Philippe Janvier: Oh, they are not extremely successful, some Lampreys are adapted to feeding on blood, they have a sucker and they attach themselves on fishes or sometimes whales, they rust skin and suck the blood, but they are not successful, they just survive by chance.
Chris Smith: Now some people say, whenever you find a fossil like this is creates two new gaps, one after and one before, so what are you hoping to find that will now fill in the rest of the missing pieces in this evolutionary chain?
Philippe Janvier: Well, I don't know exactly what could be the next step, but I think I could imagine the fossil fish which still has gill pouches and beginnings of jaws, or just the contrary, a fish which has no gill pouches but it still jawless, but we don't know, we have no idea of what kind of fish could bridge this gap between the jawed and the jawless fishes.
Chris Smith: Philippe Janvier from the CNRS in Paris finding out where fish got their gills from. The fossil, incidentally, turned up in the Miguasha region of Quebec in Canada. Well, that's it for this week, next time we will be on the trail of genes linked to cancer. In the meantime, if you're in the mood for a bit more science, this weeks Naked Scientist podcast delves into the deep, to find out what's lurking at the bottom of the world oceans, including how fish have developed their own form of spotlight, invisible to their prey, that helps them to hunt. That's the Naked Scientist podcast which is freely available from http://www.thenakedscientists.com.
Production this week was by Anna Lacey and the Division of Virology at Cambridge University and I'm Chris Smith.
Recording and transcript (c) Nature Publishing Group 2006
