Nature Podcast 4 May 2006

Introduction

This is a transcript of the 04 May edition of the weekly Nature Podcast. Audio files for the current show and archive episodes can be accessed from the Nature Podcast index page (http://www.nature.com/nature/podcast), which also contains details on how to subscribe to the Nature Podcast for FREE, and has troubleshooting top-tips. Send us your feedback to mailto:podcast@nature.com.

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Chris Smith: This week how RNA interference can help to pinpoint cancer's Achilles' heel, why climate change has got migrating birds winging their way towards extinction and the Walker wind current on the wane and a microchip sandwich, but this one's not for eating, it's a new way to make smaller and more powerful integrated circuits. Hello, I'm Chris Smith and you're listening to the 4th of May edition of Nature's podcast. We're kicking off this week with a look at a new way to pinpoint the genetic strengths and weaknesses of cancers. In other words, if you can find out what genes are driving a particular tumour or any genes that are essential to its survival, you can identify new therapeutic targets. To do this, Lou Staudt from the US's National Cancer Institute is using RNA interference. This involves producing small RNA molecules that are essentially the genetic mirror image of the gene you want to shut down. If they're added to a cell, these RNA mirror images bind to and then inactivate their target messenger RNA counterparts, switching off the expression of the target gene. What Lou Staudt has done is to put these RNAs into retroviruses which can then be used to infect cancer cells and by giving each a unique genetic barcode he can track which ones are affecting the growth of the infected cells. (Nature 441, 106–110 (2006) ).

Lou Staudt: We made a library of retroviral vectors that expressed so-called hairpin RNAs that can mediate RNA interference, which means, of course, that they knock down the expression of a particular human gene. Then we put that library of retroviruses in lymphoma cell lines and looked for which viruses in hairpin RNAs would inhibit the survival or proliferation of the lymphoma cells.

Chris Smith: Presumably, if the RNAs are switching off the cells and either killing them or making them proliferate less, those cells are harder to detect. So, how did you then find out which cells were the ones which were being targeted and therefore which were the good RNAs to use?

Lou Staudt: It was very important for our approach to make an inducible system such that we could turn on or off the expression of the hairpin RNA. We made the cells express a tetracycline repressor protein and thus, when we added doxycycline to the cell culture, we were able to turn on inducibly the expression of the hairpin so that, if the hairpin was targeting a critical gene, then when we added doxycycline, the cells would die.

Chris Smith: And how did you know the cells had gone? I guess that's a critical question because it's easy to detect when something's there but how do you detect when it's not there?

Lou Staudt: The other feature we built into our library was a so-called molecular barcode and this is very simply a 60 base pair random sequence in each individual vector in our library. We can then use those molecular barcodes to detect the abundance of each vector in the cancer cells using a DNA microray that consists of those barcode sequences.

Chris Smith: So you can see which ones are maybe making the cells grow better and which ones are making the cells grow less well?

Lou Staudt: Right. So, if a particular shRNA is toxic for cancer cells, then it's associated barcode will be missing from the population of cancer cells after a few weeks.

Chris Smith: It sounds like quite a lot of work, though, because naturally there are 30–40,000 genes in a human and you've got 7,000 vectors in your library. So, you're not quite there yet.

Lou Staudt: That's right. Our library is subgenomic but we think it is lean and mean. That is, we have focussed on certain categories of genes, notably the protein kinases, PI3-kinases, deubiquitinating enzymes, regulators of key pathways such as the NFkappaB pathway, so we have complete coverage of all those categories.

Chris Smith: It's obviously only preliminary at the moment but any surprises yet from the model system you've developed?

Lou Staudt: Well, we did know that the NFkappaB pathway was critical for a particular type of human lymphoma. What we had no idea was what was keeping that pathway turned on and that's what we discovered, that there was a set of genes that are all acting in a biochemical pathway upstream of the critical IkappaB kinase that controls the NFkappaB pathway. So, actually we did discover something quite new. I will say that we are constantly finding new surprises, so much so that it takes much longer to work out the biology of these surprises now than it is to discover them using this technology.

Chris Smith: An ingenuous way to pinpoint cancer's weaknesses. That was Lou Staudt from the US's National Cancer Institute. Now, from interfering RNA to our interference with the climate, it turns out that the warmer weather we're provoking is causing havoc for migrating birds. Christiaan Both from the University of Groningen in the Netherlands has been monitoring the populations of pied flycatchers. They overwinter in Africa and then return to Europe to breed but warmer weather means that they're now arriving too late for dinner because the caterpillars they depend upon for nourishing their young are gone before the birds are arriving home. (Nature 441, 81–83 (2006) ).

Christiaan Both: We discovered that climate change has clear implications on the population size of long-distance migrant species that wintered in Africa, pied flycatchers. We monitored nine different populations. The birds feed their chicks mainly with caterpillars and caterpillars are only available for a very short period in the early spring. So, when the temperature changes, the food availability changes. In those areas where the food peak is very early the birds do not have that much time between the arrival from their wintering areas and the start of breeding and while the food peak has changed over time, really advanced, the birds haven't advanced their arrival date because in Africa they don't know when spring starts here and so they leave there at a particular date and they arrive here on a particular date and there is not that much variance in that. So, the birds now arrive too late to profit from the caterpillar peak in those early areas while in the areas with a late food peak the birds still have the time to arrive later.

Chris Smith: And how serious is the impact on the population under these circumstances?

Christiaan Both: In those areas with an early food peak, the populations mostly disappeared. So, that's a pretty serious decline. In the areas with a later food peak, the declines are very mild. So, in the last 70 years about 10% or 20% of the population declined.

Chris Smith: What about other birds that migrate? Because this is an interesting symptom of what's happening but it can't be just confined to this group.

Christiaan Both: Yes. We now have some preliminary data from the Netherlands that show that loads of long-distance migrants that breed in forests have declined over the last 20 years and we think that that is because the food in the forest is available only for a very short period of time when the leaves start. During that period there are loads of caterpillars and if the birds miss that because they now arrive too late, that may be a reason why those long-distance migrants in forests declined so strongly.

Chris Smith: What about long-term implications?

Christiaan Both: Well, it may be the case that there will be an evolutionary change on when the birds start migration, for example. There must now be a very strong selection for early genotypes that have more offspring than late genotypes but we're not sure whether there is that much genetic variation in migration dates that really can be selected or that can change the population into earlier migration. So, that's one of the plans we are now working out.

Chris Smith: Christiaan Both. And the bad news doesn't stop there, as you'll shortly be hearing, because it turns out that human activities are also affecting the winds over the Pacific. First, though, storm clouds are brewing over the debate about mankind's impact on hurricanes and they're also brewing in UK chemistry departments, as Nature's Jo Marchant tells Anna Lacey.

Jo Marchant: Thanks. There are three stories I'm going to talk about this week and the first one is about hurricanes (Nature 441, 11 (2006) ). There were a couple of big papers in Nature and Science last year suggesting that global warming would increase the intensity of hurricanes, although not necessarily the number of storms. Last week meteorologists were meeting in Monterey, California, to discuss the question and there were some pretty heated debates by all accounts. First of all, the idea of whether even the intensity of hurricanes is increasing. Peter Webster's team at the Georgia Institute of Technology presented data hinting that not only are hurricanes growing more intense over time but that the length of the storm season has increased as well. There was also a study from researchers in the UK at the Benfield Hazard Research Centre. They've run climate simulations suggesting that half the recent rise in hurricane activity in the North Atlantic can be explained by the observed increase in sea surface temperature in the region where these hurricanes developed.

Anna Lacey: But surely now we've got so much new technology to record the evidence and data of these events, isn't the record going to be really skewed?

Jo Marchant: There is certainly an issue with the historical record of cyclones. The difficulty is having a complete enough record to understand what the past patterns and cycles could be. The alternative explanation for the rise that we've been seeing in hurricanes, if it's not global warming, is that it's just caused by a natural temperature cycle and the less information you have about those cycles in the past, the harder it is to say what's happening now and there were a few researchers at the meeting who were sticking very strongly to the line that this is nothing to do with global warming, it's just natural temperature cycles.

Anna Lacey: So, seeing as the record data is actually incomplete, where's this argument going to lead?

Jo Marchant: Well, one thing many researchers are calling for is for the databases to be brought up-to-date by including modern assessments of past storms including their intensities. That is being done at the moment but only by a few researchers and only for the Atlantic basin. So, trying to fill in those gaps as far as we can from the records we've got is certainly going to be part of the picture.

Anna Lacey: Well, moving on now, storms are also brewing in chemistry departments this week. (Nature 441, 12–13 (2006) ).

Jo Marchant: Yes. This is a sad story that's been going on in the UK for a while. A number of chemistry university departments have been closed. The latest in that line looks to be the department of Sussex University in Brighton but the chemistry department is actually fighting back. They've just launched a £1.2 million fundraising drive. They're hoping to raise money from pharmaceutical companies to keep the department alive.

Anna Lacey: But why is there so little investment in chemistry in the UK in the first place?

Jo Marchant: Well, a lot of people think it's just to do with government failing to recognise how much more expensive it is to teach chemistry students compared to other subjects such as English or history, say. You need the lab space, you need fume hoods, you need the reagents and you need equipment – that all sends cost soaring.

Anna Lacey: Even if they do get this extra money, are there actually going to be enough students to fill the places?

Jo Marchant: Well, applications are up by 40% this year at Sussex, apparently, and the university's vice-chancellor, Alastair Smith, points out that converting that increase in applications into acceptances is by no means guaranteed. It's kind of a circular argument, really. If you're not having the fresh graduates coming through – and a lot of those become chemistry teachers – if you don't have them coming through then you're getting students in schools taught by people who don't have a chemistry degree, who perhaps don't have the enthusiasm to inspire future generations on the subject. So, it's kind of all part of the same problem. We spoke to a few people in the US who said that this situation would never happen there. Chemistry is considered indispensable within US universities. At MIT, for example, every student is taught some chemistry, no matter what their subject area, just because it's seen as so important to everything, from engineering to medicine.

Anna Lacey: Well, another issue that seems to be important at the moment in the US is what to be doing about the lethal injection. (Nature 441, 8–9 (2006) ).

Jo Marchant: Yes, that's right, there's quite a debate going on in the United States at the moment over whether lethal injection is a humane way to kill people. There are three drugs that are given to the prisoners. The first is an anaesthetic which is supposed to make them unconscious, the second paralyses the body and the third, potassium fluoride, actually stops the heart. Recently there has been new evidence suggesting that with the current protocol that's used nearly half of the prisoners may actually be conscious throughout the process and therefore subjected to a very painful death.

Anna Lacey: But the fact that lethal injections might be painful isn't really new. So, what's brought this around all of a sudden?

Jo Marchant: Well, one thing that seemed to have triggered it is a paper that came out in The Lancet last year. A lot of the problem is that anyone that's medically trained – doctors, anaesthesiologists – because of their ethical stance, they won't have anything to do with the death penalty. So, generally these drugs are administered by personnel who are not medically trained. So, if the anaesthetic doesn't work properly, basically they are conscious and paralysed while their lungs stop moving and then the last drug basically causes burning, searing pain as it moves its way to the prisoner's heart and kills them. So, it's not a nice way to die and the study that came out of The Lancet last year looked at post-mortem levels of the anaesthetic in the prisoner's blood and said that in 43% of the prisoners there was such a small amount of anaesthetic in their blood that they may well have been conscious for the whole sequence.

Anna Lacey: So, what's the solution?

Jo Marchant: Well, that depends a little bit on your stance on the death penalty. Doctors and scientists, certainly, they're in a difficult ethical position. Basically, if they have nothing to do with the death penalty, many people think that that is the best hope of bringing an end to the practice because if you don't have medically-trained personnel carrying the procedure out, it can be argued that it's inhumane and therefore unconstitutional. On the other hand, if they don't participate they know that these people are dying in an inhumane way. The American Medical Association is very clear that to participate at all would violate its ethical oath 'do no harm'. So, it is a little bit of an impasse; either you help make it humane but therefore the death penalty may be more able to continue or you stand back, let people die in an inhumane way but maybe that's the best way to end the practice.

Chris Smith: Sounds like an ethical minefield. Anna Lacey catching up with Nature's Jo Marchant. Nature's Podcast, bringing the world nature to life.This is the 4th of May edition of Nature's Podcast with me, Chris Smith. If you'd like to read a bit more about the stories we're covering this week, they're available from our website at http://www.nature.com/nature and there's a complete transcript of this programme. You can find it at http://www.nature.com/podcast. Coming up shortly we'll be hearing about a new way to make much smaller microchips but, before then, here's Princeton's Gabriel Vecchi with evidence that the Pacific's Walker circulation, a tropical wind current, is getting weaker and the blame, it seems, lies firmly at our feet. (Nature 441, 73–76 (2006) ).

Gabriel Vecchi: The research team have detected a weakening in one of the main features of tropical atmospheric circulation over the last 140 years and we have found that this slowdown can be attributed to human changes to the radiative balance in the atmosphere, principally through fossil fuel burning. In many ways the structure of this slowdown, in very simple terms, would be that it looks like a tendency for a more El Nin[B1]o-like state in the atmosphere.

Chris Smith: So, in summary, pretty bad news potentially but can you just talk us through the nuts and bolts of exactly what you've measured and how you've arrived at the conclusion you have?

Gabriel Vecchi: Absolutely. The principal observations that we've used have been a record going back into the middle of the 19th Century of measurements of sea level pressure which allow us to deduce what circulation across the tropical Pacific has been like and based upon these records a clear slowdown of the winds across the tropical Pacific has emerged. We then used computer climate models to test what the source of that slowdown has been and our experiments indicate that it's very unlikely that this slowdown in the tropical Pacific circulation arose due to natural variability or changes in the solar radiation. However, the moment we start accounting for human impacts we're able to reproduce this slowdown very well with our climate models.

Chris Smith: But when do you think it's going to have an impact on the climate?

Gabriel Vecchi: Well, our computer models and the observations indicate that it is having an impact already. We've already noticed that precipitation has begun to move further to the east across the Pacific. So, while it's impossible to pinpoint the year or month or perhaps even decade in which one would see changes, we should have confidence that our model projections for further slowdown will realise and then we should start to try to understand what the impacts of that slowdown will be to individual locations.

Chris Smith: Now, given that you think this is a robust finding, what are you going to do to firm it up or take it forward?

Gabriel Vecchi: Well, we're taking it forward in a few directions, one of them is to explore what the implications of this are for weather overland, for ecosystems in the tropical Pacific, and then we also want to start looking into the path as well to see if there have been in the past changes like this which can serve as analogues to better understand what is going to happen in the future.

Chris Smith: A chilling finding with unknown consequences. That was Gabriel Vecchi from Princeton. Thankfully, here's some good news to end with because the University of Groningen Bert de Boer and his team have short-circuited the problem of shrinking microelectronics. Commenting on their findings here's Nature's Mark Peplow. (Nature 441, 69–72 (2006) ).

Mark Peplow: There's a paper in this week's Nature by Bert de Boer and his colleagues. Basically, they've managed to make an electronic device called a diode which allows current to go through it one way but not back the other way, but they've made it in a very cunning way out of carbon-based molecules and this is something people have been trying to do for 30 years, basically to try and make these devices smaller, cheaper and easier.

Chris Smith: How have they done it?

Mark Peplow: What they've done, really, is to get over one of the major problems that people have been having with this which is basically the way that you can reliably sandwich the carbon-based molecules between two gold electrodes. In the past the problem has been that when you put the second gold electrode on top, little filaments of metal grow down towards the other gold electrode.

Chris Smith: And you get a short-circuit or something.

Mark Peplow: Yes. It certainly makes the electrical properties very unreliable. Each time you make this, it's going to give you a different answer and that's not what you need for a computer.

Chris Smith: So, how have they got around that?

Mark Peplow: Well, they've got around that literally by putting a little layer of plastic in. It sounds terribly simple but in terms of manufacturing it's quite a big step, really. This layer of plastic, it's about 20 billionths of a metre thick but it just stops the top gold electrode growing down, stops those little filaments forming.

Chris Smith: Can you just give us a rundown on the nuts and bolts of how they made these incredibly small circuits?

Mark Peplow: It's like making a sandwich. You start off with your silicon wafer – so, that's like a slice of bread – and you butter it with some gold – that's your first electrode. Then basically they put kind of a template on top and into that they pour the carbon-based molecules. They're called alkanethiols. They're basically long chains of carbon with a sulphur atom on the end. The sulphur likes to stick to the gold and so when you take the template away, it looks like you've got a carpet, really. You have the gold on the bottom, sulphur atoms are stuck on top of the gold and then you have these long, wavy carbon backbones sticking up into the air. Then on top of that you put a nice thin layer of plastic to protect the whole thing and then, finally, you top it off with another gold electrode. And it's very cheap and easy to do as well and it could be easily integrated into the way that we make silicon chips at the moment.

Chris Smith: So, it is something that theoretically you could see rolled out on the production line before too long.

Mark Peplow: That's right. There are obviously a lot of other hurdles to get over in terms of using molecular electronics but this has been quite a big one. The key thing is it potentially allows you to get over one of the main barriers that allows computer chips to keep on shrinking. Using carbon-based molecules in these chips instead will allow us to keep going smaller quite a lot further.

Chris Smith: What about the stability, though, Mark? A key question here is is this thing going to survive the rigours not only of manufacturing but then being in a very hard-pressed computer chip. Will it survive for a long time?

Mark Peplow: Well, this is the amazing thing, actually. They found that when they were making these things, over 95% of the molecular junctions that they made – that's the connections between the gold, the organic molecule and the other gold electrode – worked really well. That's an amazingly good yield. The other thing is that it seems like they last for months at least and they don't seem to lose their properties. So, it's a big step for scientists.

Chris Smith: Let's hope their microchip sandwich lands butter-side up. That was Nature's Mark Peplow commenting on the announcement this week by Bert de Boer and his colleagues of a new way to shrink microelectronics yet further.Well, that's all for this week and thank you very much for listening. If you have any feedback about this podcast, then do drop us a line to mailto:podcast@nature.com. Next time we'll be tying ourselves in pseudo-knots and also looking at an impact of meteoric importance.Until then, though, if you're in the mood for some more science, this week's Naked Scientists podcast looks at erasable tattoo technology and a fleet of football-sized formation flying satellites. That's the Naked Science podcast which is freely available from http://www.nakedsciences.com.

Production this week was by Anna Lacey, the Cambridge University's division of Urology, and I'm Chris Smith.

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Recording and transcript (c) Nature Publishing Group 2006