Nature Podcast

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Kerri Smith: Coming up this week, the brain cells helping songbirds to sing along.

Richard Mooney: What we found is that their individual nerve cells that switch rapidly from an auditory state to a motor state as the bird goes from listening to singing.

Adam Rutherford: And a new way of bonding an unreactive uranium compound.

Polly Arnold: The uranyl starts to attack other small organic molecules in new and unusual ways that we were not expecting. This is very unusual for uranium and we are so excited by it.

Kerri Smith: And lab-lit enthusiast Jennifer Rohn asks why there are not more scientists starring in novels.

Jennifer Rohn: Science news is everywhere, yet its practitioners are largely absent from the world of our imagination.Music

Kerri Smith: This is the Nature Podcast. I am Kerri Smith.

Adam Rutherford: And, I am Adam Rutherford. HIV/AIDS has claimed the lives of more than 25 million people since its discovery in 1981 and an estimated 33 million people currently live with the disease. Understanding the mechanisms of infection of this rapidly evolving virus, is key to developing treatments for the pandemic. A team led by Paul Bieniasz from Aaron Diamond AIDS Research Centre in Rockefeller University in New York and Stuart Neil now at King's College London have discovered a molecule that ties virus particles to the infected cell. This tetherin prevents the virus from infecting other cells. I spoke to Paul Bieniasz and asked him how their molecule prevents the virus from spreading. Nature advance online publication (16 January 2008)

Paul D. Bieniasz: So, when HIV infects a cell it in essence makes a DNA copy of itself, which is inserted into the host cell genetic material. That then programs the cell, in effect, make new viral particles, which assemble at the surface of the cell and in doing so, they push through the membrane and bud into the extracellular milieu. Intuitively, one would think that the viral particle would be free to go off and infect new cells. That is when tetherin begins its action. It in fact stops this seemingly inevitable parting of the ways of the cell and virus particle and causes retention of the viral particle on the cell surface.

Adam Rutherford: So, tetherin is actually as the name suggests, tethering these viral particles to the cell, how did you discover this molecule?

Paul D. Bieniasz: When we analyzed a number of different types of cell that we infected with HIV-1, what we found is that sometimes you needed the presence of a small viral protein called Vpu in order to get efficient virus particle release. In other cells, the viral protein Vpu was completely dispensable and if you deleted it from the viral genome, then virus particle release would occur extremely efficiently and so, what we did is we used fairly recently developed technology to simply compare what genes are expressed in cells where you need Vpu for virus particle release and in cells where you do not, and in doing so, we came up with four candidates in effect. One of them was much more compelling than the others and from there we applied various tests to this protein and found that it in fact was responsible for retaining virus particles on the cell surface.

Adam Rutherford: Okay, so what does this mean for potential therapeutics, if you can retain the virus from spreading?

Paul D. Bieniasz: In principle, this is a target at which we could aim antiviral drugs. We do not know at present how effective such drugs would be in any given viral infection, but if one could for example prevent the Vpu protein of HIV from antagonizing the tetherin mechanism, then in effect viral infected cells should be less good at releasing viral particles, and in principle that should inhibit the spread of the virus infection from cell to cell. Now, our knowledge of how the whole thing works, how Vpu works, how tetherin works is at present rather primitive. We have only known of the existence of this molecule for a few months, but in principle it is a viable target at which to aim drugs. I think one of the things we are going to do next and this will be quite important is to determine whether tetherin works on a lot of different viruses, if it does and that obviously makes it much more broadly applicable in terms of potential antiviral therapies.

Adam Rutherford: Paul D. Bieniasz of the Aaron Diamond AIDS Research Centre and Rockefeller University in New York.

Kerri Smith: A new target for anti-HIV drugs could hold some promise for the millions around the world living with HIV - around 1 in 200 people. But 1 in 5 people worldwide live with chronic pain and a new treatment for this condition is the subject of another report in Nature this week. Charlotte Stoddart has more.

Charlotte Stoddart: Many people with inflammatory diseases or nerve damage live with chronic pain. There is currently no way to treat this pain without side effects, but a study published in Nature this week suggests a new class of drugs, which the researchers hope will kill the pain without sending patients to sleep or getting them addicted. The study identifies which particular component of a receptor found in the spine deal with the pain enabling researchers to target them without stimulating other components, which cause the unwanted effects. I spoke to author Hanns Ulrich Zeilhofer from the University of Zurich. He explained to me how this spinal receptor acts as a filter controlling which pain signals are relayed to the brain. Nature 451, 330–334 (17 January 2008)

Hanns Ulrich Zeilhofer: What is well known is that under normal conditions the spinal cord functions as kind of a filter, which prevents most of the painful signals coming from the periphery to reach the brain. Now, what is known is in chronic pain this filter becomes compromised. During chronic pain, mediators are produced in the spinal cord, which diminish inhibitory pain control.

Charlotte Stoddart: What new light does your study shed on how the spine controls pain?

Hanns Ulrich Zeilhofer: We have now identified which inhibitory receptors are involved in this gate control of pain. Fortunately, these receptors can be targeted by drugs.

Charlotte Stoddart: So, what did you and your team do to find the receptors responsible for this gate control?

Hanns Ulrich Zeilhofer: So, the basis for our study was the development of different genetically modified mice and these mutant mice allowed us to identify the receptors for an inhibitory neurotransmitter for gamma-aminobutyric acid, which are responsible for this pain control. So, what we did is, we used these mice, we induced an inflammatory pain or a neuropathic pain condition and treated these mice with drugs which target these receptors and by using four different kinds of these genetically modified mice, we could identify which one of these receptors were responsible for the pain control.

Charlotte Stoddart: So, these mice had different parts of the GABA receptor damaged and then you injected this drug into the spine to see what effect it had, that compound that you injected is a benzodiazepine closely related to Valium, but crucially unlike Valium it does not act as a sedative. Why doesn't it have this effect?

Hanns Ulrich Zeilhofer: Classically, benzodiazepines like diazepam, they should not be used in chronic pain patients, and the reason is they cause a sedation, they are sleep promoting. During chronic treatment they lose their efficacy, they cause tolerance and patients can even become addicted. Now, most of these unwanted effects arise from the brain and we have now found a way to selectively target the benzodiazepine receptors in the spinal cord. GABA (Gamma-aminobutyric acid) is an important neurotransmitter in the spinal cord, which controls pain. Fortunately, these benzodiazepines act on different types of GABAA receptors, and with the use of the mutant mice, we could show that for the analgesic action it is only a subset of GABAA receptors that are required for analgesia if those that are expressed in the spinal cord.

Charlotte Stoddart: And, this then suggests a whole new class of pain-killing drugs designed to target these spinal benzodiazepine receptors, how would these compare with standard pain killers such as morphine?

Hanns Ulrich Zeilhofer: Yeah, we have done one set of experiments where we have compared one such selective compound with morphine and what we found was during an acute treatment both drugs were about equally effective, but when we treated the animal for a prolonged period for about nine days we found that morphine had completely lost its activity while the compound we had tested was still effective; just the same efficacy as on the first day of treatment.

Charlotte Stoddart: So, finally, what needs to be done next before we can develop this new class of analgesic drugs further and bring them to clinical trials?

Hanns Ulrich Zeilhofer: Well, what we have shown is which receptors need to be targeted and the good news again is that pharmaceutical companies are already working on such compounds because these compounds should also be non sedative anxiolytics. So, it is now a challenge for medicinal chemistry and pharmaceutical companies, drug companies to develop compounds which selectively act on these benzodiazepine receptors, which are responsible for the spinal analgesia. There are already a few such compounds published, but they are either not selective enough or they are not stable enough in the human body. So, this is again something that needs to be addressed by medicinal chemists.

Adam Rutherford: Hanns Ulrich Zeilhofer ending that report by Charlotte Stoddart. In just a moment Geoff Brumfiel talks to the team behind a clever piece of chemistry that could one day help us store nuclear waste more efficiently, but first postdoc and science writer, Jennifer Rohn takes to the Podium to demand more novels with scientific protagonists. Nature 451, 128 (10 January 2008)

Jennifer Rohn: It all started in Seattle in 1990. A fellow graduate student slipped me a battered paperback that was doing the rounds. It was 'Cantor's Dilemma' by Carl Djerassi, not science fiction, but a novel about contemporary scientists. Just as at school when kids used to circulate racy novels with a sexy biz underlined, someone highlighted a few scenes of explicit hardcore biochemistry. It was thrilling to read literature about my own world for the first time. I wanted more. And the alien anthropologist armed only with our fiction bestseller lists might conclude 'the detectives were all the Earth. This alien could easily inspect novels for months and never work out that humans do scientific research. Science news is everywhere, yet its practitioners are largely absent from the world of our imagination. If fiction is a mirror held up to our culture, scientists are its vampires. They lurk in the shadows casting no reflection. What about science fiction. True, it has been going for centuries, but it is not lab-lit, which I define as any story with scientists as central characters set in a realistic past or present world. Most science fiction lack scientists and those that have scientists usually practice research that is currently impossible. Forensic dramas feature scientists too, but there is far more to science than crime. On the other hand, general lab-lit fiction emerges only once every year or so. If you think I am exaggerating, try to name more than three trade fiction novels, where scientists as central characters ideally set in a lab or a field station. Hard, isn't it? There are in fact fewer than a hundred. I think that this is because most book industry folks are arts and humanity graduates who do not care much for science. 100 novels about the endeavour that shapes and explains our world is not enough. I would like to see more stories about scientists written, published, read, and made into films. After all, the laboratories are tense, passionate, dramatic, and competitive setting with great scope for adventure, and more seriously fiction is an excellent way in for people who fear and distress science. Just as websites like MySpace have helped make musicians, rock stars from the comfort of their own bedroom, I am hopeful that lab-lit authors can exploit the internet to circumvent the publishing industry altogether. Readers who like a lot of science in their fiction can now connect online with like-minded writers. So, I am looking forward to getting my hands on a lot more lab-lit to read, underline, and pass around the common room in the future.

Adam Rutherford: That was Jennifer Rohn, cell biologist from UCL and editor of


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Adam Rutherford: You are listening to the Nature Podcast. Next, Geoff Brumfiel discovers a neat chemical trick for manipulating and possibly storing uranium.

Geoff Brumfiel: Most of us know about uranium's nuclear properties. Its radioactive isotopes are used in power reactors and nuclear weapons, but uranium's chemistry is in many ways more mysterious. Chemists find it tough to predict how the large cloud of electrons that surround the atom will behave. In this week's Nature, a team of chemists reports on a new way of bonding inert uranium dioxide or uranyl to another compound. I spoke with author Polly Arnold of Edinburgh University to learn more about the new reaction and what it might tell us about uranium. Nature 451, 315–317 (17 January 2008)

Polly Arnold: When you dissolve any uranium compound in air, in the atmosphere, it always ends up as the uranyl ion when it is in solution, so in water or other solvents or things like this.

Geoff Brumfiel: And this ion is somewhat problematic in that it is not very reactive right?

Polly Arnold: Yeah, so it forms these extremely strong bonds to the two oxygens that it picks up and makes this linear di-cation, yeah it is extremely inert and therefore very interesting as a challenge.

Geoff Brumfiel: Now, it seems to me that, you kind, of want uranium to be inert because then it is not doing anything, but this is a problem for nuclear waste?

Polly Arnold: You would want it to be inert if only it was not so water soluble in this inert form.

Geoff Brumfiel: How is that a problem?

Polly Arnold: It means it is very mobile. So, once you reach this Uranyl dication, it is very water soluble and it can move around in ground water and it can leech out of natural uranium mining areas and also out of perhaps nuclear waste storage sites, although I seem that is not very likely to happen.

Geoff Brumfiel: You have figured out a way then to make the uranyl atoms bond to something else is that right?

Polly Arnold: What we have done is in a collaboration with Dr. Jason Love's group here, they make a rigid pacman-shaped molecule, which binds metals in a particular shape, like a mouth-shape and what we have done is put the uranium ion into it. When we do this and then we do some more chemistry on it, the uranyl starts to attack other small organic molecules in new and unusual ways that we were not expecting. This is very unusual for uranium and we are very excited by it.

Geoff Brumfiel: And so, what do you hope to react it with once you have got it into this compound?

Polly Arnold: So, the uranyl is uranium with two oxygen atoms, one either side and when we put it in the pacman, one oxygen sits inside the mouth and is protected and the other oxygen sticks out like a packman's horn and that is the oxygen that suddenly becomes activated to do this other chemistry and pick up small molecules from the solution. So, we were very lucky that it picks up one of the other organic molecules that was floating around in the solution. What we want to do now is see if we can push it just one electron further and to completely remove that top oxygen that would be really unusual.

Geoff Brumfiel: I see, and so if you can remove that oxygen you are saying that you will have even more control over the uranyl atom, is that right?

Polly Arnold: Exactly, it is a very esoteric goal, you know, I cannot imagine it being useful for anything, but you know that is not the reason to try and do chemistry. We always try to do the most unusual thing we can.

Geoff Brumfiel: Can this have any uses I mean, I have seen that there may be some far-off applications for reacting uranyl with other molecules?

Polly Arnold: Okay, so these compounds at the moment, we hope they are useful as models for helping people understand what happens when uranium gets precipitated out of ground water or out of contaminated water, but we could not use these compounds to do that process ourselves, because they are too reactive with water. They would fall apart in water. The aspect that I think might be very interesting for them in the future is to look up them as models for plutonium compound. Plutonium is so highly radioactive it's extremely difficult to do chemistry on it. So, it would be very nice to use these molecules as rather good models for plutonium.

Adam Rutherford: Polly Arnold of University of Edinburgh.

Kerri Smith: Finally this week, brain cell sing along. If you are a songbird, it is pretty important to be able to communicate with your chirpy chums by singing a distinctive song and recognizing other similar ones you hear around you, but how do you know that the other songs you are hearing are similar to the ones you sing yourself, and how do you learn these songs in the first place. In primates, mirror neurons have been found that are active when a particular movement is seen or performed. The idea is that there are neurons in the songbird brain that act in the same way monitoring the match between songs heard and songs performed. I called Jon Prather and Richard Mooney, half of the team at Duke University that has hit upon these illusive brain cells. Richard Mooney first of all. Nature 451, 305–310 (17 January 2008)

Richard Mooney: What we found and Jon can tell you about this in greater detail. This took a really heroic technical effort to find this, because we were working with wild songbirds. What we found is that in this high-level region in the forebrain of the bird, a structure known as HVC that is important to both singing and song perception and song learning that there are individual nerve cells that switch rapidly from an auditory state to a motor state as the bird goes from listening to singing the same song or a very similar song in its repertoire and the timing of the activity is exactly the same whether the bird is listening to the song or singing the song.

Kerri Smith: Turning to you, Jon Prather, could you tell us a little bit more about then this heroic technical effort you have been making, how on Earth did you find these neurons, it must have been quite tricky to see what they were doing while these wild birds were in the middle of singing?

Jonathan F. Prather: It was tricky. We implemented a technology in which we were able to place a very small micro-drive atop the bird's head and this device was 1 gram in mass and contained motors which allowed us to change the position of electrodes very carefully. So, we could place our electrodes into the nucleus that we were interested in, into HVC and record from individual neurons that we identified by stimulating elsewhere in the brain and then at the end of the day we could use that motor to retract our electrodes and thus do minimal damage during the overnight period when the bird was hopping or otherwise going about its normal behaviour.

Kerri Smith: And it was possible then to record from these same neurons and you found them doing what exactly?

Jonathan F. Prather: We demonstrated that there was a sensory motor correspondence both in the song that was represented one among many and its vocal repertoire and in the timing of the neural activity used to represent the occurrence of this gesture, whether it occurred through singing or through sensory detection as the bird heard the same song.

Kerri Smith: So, effectively these neurons are not picky as to whether the bird is hearing or singing a particular song, they just react in any case?

Jonathan F. Prather: Yes, that appears to be the case. These neurons effectively represent the occurrence of the gesture itself regardless of whether it is being performed or observed and curiously we also observed that these neurons were not picky with regard to the identity of the bird performing the gesture. The neurons were representing the gesture regardless of which bird performed it.

Kerri Smith: What function are they serving if they are not able to tell the owner of the voice?

Richard Mooney: We think that they are serving different roles in different context. So, they are two states in which they are active; one when they are listening to other birds and one when the bird itself is producing its song, and they show an equivalence in the listening state when they are hearing other birds in the neighbourhood sing, these neurons could be very effective decoding those songs. They could allow the bird to use activity in these neurons to select a song from its own repertoire to sing back. So that might be the basis of, sort of, an online matching system by the bird. That certainly one way these could be active and the other is that when the bird sings, the motor system is effectively creating an emulation of what the activity pattern would be if it were being evoked by listening. It appears that the motor circuits in the bird's brain generate sort of an image of what the auditory signal should be that would be created in association with the sound and that is a very important idea for enabling certain forms of learning.

Kerri Smith: So, not only as an online, kind of, gauge of what other songs are out there in its environment, but it can also use this image, this copy of the song to readjust its own vocalizations to fit?

Richard Mooney: Exactly, these neurons are perfectly suited to enable the motor system to generate an estimate of the feedback that should happen when the bird sings, i.e., the auditory feedback and they can compare this signal to the actual feedback to correct minor errors in vocal performance.

Kerri Smith: It is tempting to draw parallels between birds learning songs and humans and other primates learning to communicate via mirror neurons, is this is a fair comparison to make?

Richard Mooney: I think it is a very fair comparison. Birds are solving exactly the same problem we solve when we use speech sounds to communicate, at least in terms of low level aspects of communication. They are certainly achieving location and identity through these songs and they are solving the same problem in learning to sing that we solve when we learn to speak. They are using an auditory model, they are mimicking it, and they do so by using auditory feedback to match their own vocalization to the model that they are trying to copy. These neurons seem to play a role or certainly positioned in the part of the brain where they could play a role in both the communicative aspects of vocalization and the learning aspects. So, I think the analogies and perhaps even the homologies are very strong between the bird and the primate and even the human.

Adam Rutherford: Richard Mooney and before him, Jon Prather. They are both at Duke University. That is it for this week. To play us out, here is some songbird karaoke, three song snippets from each of two of the birds that Richard and Jon's team used in their study. I am Adam Rutherford.

Kerri Smith: And I am Kerri Smith. Thanks for listening.

[Sound of Science]


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