Nature Podcast 29 November 2007

This is a transcript of the 29th November 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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Kerri Smith: This week, we find out about the climate on Venus, but even if you are desperate for some winter sun we do not recommend it.

Håkan Svedhem: It is a very hot and a very dense atmosphere. It is more than 400 degrees Celsius and composed almost entirely of carbon dioxide. So, it is a very unfriendly climate on Venus.

Mike Hopkin: And a new technique helps researchers puzzle out the gateway to the nucleus.

Michael P. Rout: Our approach is rather, now I guess, is to solving a crossword puzzle. We just gained lots and lots and lots and lots of clues about how this thing is put together, and at one point we stopped to get enough information that we could actually start to solve all the clues.

Mike Hopkin: More on that later in the show.Music

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

Mike Hopkin: And I am Mike Hopkin. First this week, new leads in the search for diabetes drugs. The disease accounts for 5% of deaths worldwide each year and the World Health Organization warns that without urgent action that figure will increase by half over the coming decade. Many cases are linked to unhealthy eating habits and cutting the calories is the best strategy for diabetics or those at risk of developing the disease, but a new generation of drugs aims to mimic the effects of calorie restriction by activating the same pathways. The leading candidate, resveratrol is currently undergoing clinical trials, but researchers have now found a new class of molecules that could do the job even better. Here is Christoph Westphal of Sirtris Pharmaceuticals in Massachusetts. Nature 450, 712–716 (29 November 2007)

Christoph H. Westphal: What we have shown in this paper is that we can find molecules completely unrelated in structure to resveratrol and roughly one thousand times as potent. One year ago, we published an article in Nature showing that resveratrol extended the healthy lifespan of mice at a high-fat diet. Not only did resveratrol have those positive effects, but it also seemed to lower glucose and insulin and increase exercise tolerance in rodents.

Mike Hopkin: So, what sort of thing does resveratrol do for the people who take it, what kind of benefits does it give, and are your compounds potentially better than resveratrol?

Christoph H. Westphal: Yeah, so what is particularly exciting about this study is that as far as we know it is the first time that anyone has designed small molecules, specifically to target a gene that controls the ageing process, SIRT1. The founding member of sirtuin family of enzymes has been shown in virtually every organism to mediate the beneficial effects of calorie restriction and to extend healthy lifespan. What is particularly exciting about this new paper is the ability to activate SIRT1, not only with resveratrol, but also with one thousand times more potent molecules, in other words at a thousandth the dose.

Mike Hopkin: So, it does not potentially mean that somebody taking a molecule like this would get the benefits of a calorie-restricted diet without necessarily having to follow such a diet?

Christoph H. Westphal: Well, it is a great question. What we always say is when you go to the doctor and you have type 2 diabetes, your doctor will tell you to calorie restrict or diet and if that does not work they will tell you to exercise. What we know now in humans and in various models is when you calorie restrict or you exercise, you induce SIRT1, the gene that controls the aging process and so, we believe when we provide resveratrol or these one thousand times more potent molecules to animal models of diabetes that basically we are mimicking several of the beneficial effects of calorie restriction.

Mike Hopkin: So, you gave these compounds to mice as an animal model of diabetes, what sort of in real terms happened to the mice when they were given these drugs?

Christoph H. Westphal: So, what is particularly exciting is there are three gold standard models of diabetes, the Diet-Induced Obesity or DIO mouse, the ob/ob mouse, and Zucker fa/fa rat. Those are highly predictive of positive effects in type 2 diabetics and what we showed in this paper is that not only did we lower glucose, which is very good of course for a diabetic, but we also improved insulin sensitivity, in other words we lowered insulin levels, which is something that doctors really look for when they are treating diabetics.

Mike Hopkin: What kind of patients would these drugs be aimed at, would they be mainly for people who have already been diagnosed with diabetes or could they potentially also be used for people who might be in a high-risk group?

Christoph H. Westphal: We believe the initial indication would be type 2 diabetes or age-associated diabetes, but one of the things that are particularly compelling about this approach is that there are many diseases of aging that seemed to be beneficially affected, by SIRT1 activation. There have been numerous reports showing that SIRT1 activation is beneficial in neurological disorders such as Alzheimer's and ALS, in cancer, in inflammation, and so what we really think as exciting as the idea of targeting SIRT1 activators to multiple large market opportunities.

Mike Hopkin: And, just finally, do approaches like this offer the potential, you know, to ultimately remove diabetics dependence on insulin and the whole routine of daily injections that many diabetics have to go through?

Christoph H. Westphal: Yeah, that is a great point. Most diabetics begin on metformin and ultimately move to insulin therapy, which has a lot of drawbacks. Insulin increases weight and ultimately is only effective for perhaps a decade or 15 years, when even insulin therapy begins to fail. Most doctors would really prefer to put their patients on a regimen that increases insulin sensitivity. That is why when you first present with type 2 diabetes to your doctor, your doctor says calorie restrict and if that does not work, exercise. Both of those are natural mechanisms that are safe, that induce SIRT1 and the sirtuins that insulin sensitize. Our belief and hope is that ultimately SIRT1 activators could be front-line therapy and would really mimic these natural and safe mechanisms that we know work in nature.

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Kerri Smith: And now, to the results of the Venus Express. No, it is no new musical, but a voyage to Earth's planetary twin. Geoff Brumfiel reports on what it found.

Geoff Brumfiel: Venus is a planet literally shrouded in mystery. Its surface is hidden by a thick layer of carbon dioxide, but the second planet from the sun used to be much more like Earth according to Nature's astronomy editor, Leslie Sage, who spoke to me from our Washington office. Nature 450, 629–632 (29 November 2007)

Leslie Sage: It is a near twin to Earth in mass and radius and it is fairly close to us in the Solar System. So, the initial conditions on both planets had to be quite similar. Now, Venus has a massive atmosphere with essentially no water and we have, compared to Venus, relatively rarefied atmosphere and lots and lots of water, and how did these changes come about is a very interesting question.

Geoff Brumfiel: To help answer that question, the European space agency sent the Venus Express orbiter to take a look. Now, nearly two years after its launch, Nature has published a series of eight papers that will help shed some light on the planet. I talked to Håkan Svedhem, Venus Express' project scientist to learn more about what this spacecraft can do and what it has found in its first year on the job. What was the Venus Express able to do that the other spacecraft, I guess there have been about 30 now that have gone to Venus have not been able to see?

Håkan Svedhem: Yeah, we are really exploring these features which was discovered fairly recently that some infrared wavelengths ranges, what you call the infrared windows, we can actually probe very deep down into the atmosphere. So, we can map out winds in three dimensions in the atmosphere and this is giving us a very good understanding of how the dynamics works, how the circulation works.

Geoff Brumfiel: And, what have you found about the circulation on Venus, what makes it interesting?

Håkan Svedhem: We see that now we have the behaviour which we believe indicates that there really is a Hadley type of circulation in the mid and the lower atmosphere, and this process seems to be very similar to those indoors in the mid and lower atmosphere. Those are called Hadley cells, the circulation going from the equator moving towards the pole and then, at the Earth, this air is descending at the mid latitude, while on Venus it is progressing to a more northerly or southerly for that sake latitude before it is descending again and only this is closing its loop at the lower altitudes, and for the circulation in the upper atmosphere we are using a specific technique to study the air glow.

Geoff Brumfiel: What is air glow?

Håkan Svedhem: Air glow is molecules that are excited and emit light at specific wavelengths. By looking specifically at these wavelengths we can see these dynamic features.

Geoff Brumfiel: So, you can use them to see how the circulation in the upper atmosphere works?

Håkan Svedhem: Yes, this is of course interesting feature in itself, but what we have applied it for now is really to determine the wind speeds and the wind directions in the upper atmosphere.

Geoff Brumfiel: I understand that one way the Venus is different than Earth is that there are these huge vortexes at each of the poles in the atmosphere, has Venus Express looked at these and has it been able to say anything new about them?

Håkan Svedhem: Yeah, we have got really spectacular images of these vortices. We are concentrating on the south polar region, because that is what we have best in the field of view due to our orbit and we can follow the dynamics in these vortices for up to 10 hours and since we can see in three-dimension, we can really see all the details at all different levels and they not only give very pretty pictures, but they also teach us very much about how the air is circulating in this very special region of the planet.

Geoff Brumfiel: So, what are these? I mean are these like giant planetary hurricanes at each of the poles?

Håkan Svedhem: They look very much like hurricanes indeed, but they are much bigger in extension. They are several thousand kilometres across. So, they are really larger than the Earth-based hurricanes and exactly how they are driven we do not know yet, but we are studying on that and that is of course coupled to the general circulation of the planet.

Geoff Brumfiel: One similarity which you have also mentioned in this paper to the Earth is this question of whether or not there was lightening on Venus and I understand that you have gotten some measurements now that indicate there is lots of lightening more than there actually is on Earth, is that right?

Håkan Svedhem: Yes, it is true. We have very much lightening on Venus. It is very, very good that we have been able to clearly say that. It has been speculated. There have been indications from previous missions to Venus that there should be lightening, but it was never been really 100% proven and now we have really been able to see that with our magnetometer, which picks up signals when we are close to the planet and this is at quite a high rate and we are now try to find out what the strength is of these lightening because it is an important element of the environment of Venus.

Geoff Brumfiel: So, how much longer is Venus Express going to be operating?

Håkan Svedhem: We have now extended the mission. Basically, our first basic mission was until October this year and we have now extended the mission till May 2009. We will look more in detail to get a better global coverage on the measurements we are doing and we will also look into comparing images with previous images we have already taken to see if we can find any indications of volcanic activity on the surface.

Mike Hopkin: Håkan Svedhem talking to Geoff Brumfiel about Venus' climate and for more on our own climate, you can check out our new climate change podcast, listen or subscribe for free at http://www.nature.com/climate, and from one complex system to another, we turn to the inner-workings of our own cells.

Kerri Smith: One problem for biologists has been that many techniques cannot deal with the size and complexity of a cell's component parts, but now a team led by Mike Rout of the Rockefeller University in New York has devised a new method they liken to a crossword puzzle in order to suss out one of the trickiest parts, the nuclear pore complex. This structure acts as the gateway to the nucleus allowing cargos to be transported back and forth in the DNA. Before telling me about the new method, he gave me a whirlwind tour of the nuclear pore complex. Nature 450, 695–701 (29 November 2007)

Michael P. Rout: The nuclear pore complexes are the only mediators of exchange between the nucleus and the cytoplasm in the cell. So, of course, the nucleus contains all the DNA in the cell and all the instructions to tell the cell what to do. So, in order to get into and out of the nucleus you need to go through this nuclear pore complex. Each nuclear pore complex is very large. They are made up of about 480 individual components. It is made of eight interconnected spokes that surround a hole about 30 nanometres across. Through that hole or tube, that the exchange occurs between the nucleus and cytoplasm.

Kerri Smith: So, it is basically shuttling cargos than back and forth from the DNA that has been stored in the nucleus?

Michael P. Rout: That is right. So, it is a very effective gatekeeper for the nucleus.

Kerri Smith: Now, it is clear that this structure is fairly large and fairly unveiled and people have been exploring its structure for a while, why has it been so difficult to elucidate exactly what is going on there?

Michael P. Rout: Right, yes, I was one of them, of course, running up against the same barriers, which is that firstly it is very large in terms of these things. The kinds of techniques that are used to study macromolecules in cells and things like NMR and x-ray crystallography and of course they have revolutionized our understanding of cells, but they tend a lot to look at smaller things and when you get to very large things you start to run into problems and the nuclear pore is such a problem; they are just too big for those kind of techniques. The other problem is that it is rather sloppy, if you like it. It is able to stretch and bend and about a quarter of its components are intrinsically disordered. They are long thin wiggly filaments that just wave around in the Brownian breeze. So, our techniques come up into problems if the things we are trying to look at are not terribly ordered, because it is very hard to look at one single item from many cells, because they are so small and very difficult to image.

Kerri Smith: What have you done then to be able to overcome these problems of very small and very disorderly structures?

Michael P. Rout: Our approach is rather now I guess to solving a crossword puzzle. The kinds of experiments that are available to biologists and biochemists and biophysicists can actually be reengineered or tailored to generate spatial information about macromolecular complexes and that if we do enough of them and lots of different kinds, enough kinds of them, we can actually gain enough information about, in this case, the nuclear pore complex, but we would actually be able to solve the structure. So, it is a bit like looking at the nuclear pore complex as a crossword puzzle. Normally, the kinds of experiments we used generate fairly low-grade spatial information, which is why perhaps previously that had not really been used to solve structures, but like any clue in a crossword puzzle, each clue in itself is often not sufficient to solve that word, sometimes it is, but usually it is not. What you need, however, is that all the information is intersecting. It is one single crossword puzzle and of course this is one single nuclear pore complex. So, what we did is we just gained lots and lots and lots and lots of clues about how this thing is put together and at one point, we stopped to get enough information that we could actually start to solve all the clues. What we did is Andrej Sali, a part of group has put together some software, which can actually look at all this information and interpret it into structure. So, that software is really our crossword puzzle solving software if you like.

Kerri Smith: I was going to say you sound as if you have set your analogy one step further you have devised the clues and then you have had to sort of invent the grid to go with them?

Michael P. Rout: Absolutely, yes.

Kerri Smith: So, I am gathering that this has been quite a mammoth task for quite a large team of you, how long as it all taken you?

Michael P. Rout: The first experiment to look at the relative arrangements, proteins in the nuclear pore were done about nine years ago. These were our first pilot tests and it has been ramped up in the year or so after we first started. So, it has really taken eight to nine years to get to this point.

Kerri Smith: You must be overjoyed to have it done?

Michael P. Rout: Oh, yes. This has been a celebration literally halfway around the world, because many of the people who were involved in this have now got on to other laboratories because it has taken so long, and but we are actually trying to put together a big get together in the New Year some point and have a big celebration. There has been a lot of hard work, you know, a tremendous one.

Kerri Smith: So, finally then, do we now understand how it all fits together, what do we still need to resolve?

Michael P. Rout: You can look at this as a first draft map. By no means do we consider it complete or perfect, I mean we certainly have a position for every protein in the nuclear pore complex, but what we would like to do now is get a much better idea of the position of every protein and so on and so forth. So, there is a lot of interesting questions about how you make these structures and how they might be related to each other that we can look into. Also we can look into the arrangements of the gating proteins that actually regulate what goes in and out of the nuclear pore complex and actually try and understand how that gating process occurs, because in fact we really do not understand how that gating works. At the moment, we have just a static snapshot of an average nuclear pore complex, but where we would like to go of course is to animate that to actually try and put information that we are gathering in our laps on how things actually move back and forth across the nuclear pore and actually put back onto the map and start generating, if you like movies, of how things actually move across the nuclear pore complex.

Mike Hopkin: Mike Rout there and you can check out Nature's special video coverage of that research by visiting http://www.nature.com/nature/videoarchive.

Kerri Smith: And on the subjects of solving puzzles and cracking codes, our Podium speaker this week is Cory Doctorow, editor of popular techie blog, Boing Boing. He gives us his take on the challenges of safe digital encryption.

Cory Doctorow: In the debate over copyright. Many argue about whether the anti-copying systems and DVDs, digital music and PDFs go too far, but not many people ask the most important question; is it scientifically possible to prevent copying of a digital document? In cryptography, there is always a sender, a receiver, and an attacker. All are presumed to be in possession of the cipher text, the scrambled message. It is a fool's paradise to assume that the attackers have not been able to pick up on your satellite signals, radio messages or internet traffic. Likewise, all are presumed to be in possession of the cipher used to scramble the message. Peer review is the only way to harden a cipher against attack and broad peer review works better than private in-house peer review. As computer security guru, Bruce Schneier says anyone can invent a cipher that is so secure that he himself cannot break it. That does not mean that it is unbreakable, just that it is unbreakable by people dumber than the inventor. There is only one piece of information that the sender and the receiver share and that the attacker is excluded from: the key. The key is the short mathematical string you feed to the cipher in combination with the cipher text to descramble it. For so long as the key is known only to the sender and the receiver, the attacker can eavesdrop all she wants and she would not be able to decrypt the message and this is why copy-prevention schemes are always broken usually by bored teenagers who crack them for giggles before breakfast. Whether its Blu ray or Adobe ebook encryption, all copy-prevention systems have to first give you the keys to decrypt the cipher text. If you cannot decrypt your DVDs you cannot watch them and so you would not buy them and second, prevent you from using the keys to decrypt the cipher text except is permitted by the publisher i.e., allowing you to watch the movie, but stop you from saving it to your hard drive. It is a fool's errand. If you are the attacker, then it is insane to give you the keys. Designers of these systems try to hide the keys in software or hardware, but this same software or hardware is then delivered to your home or your lab, where you may have everything from a debugger to an electron tunnelling microscope with which you can extract the keys. It is like keeping the bank vault in the safecracker's living room. Once the keys are extracted, all bets are off. The late keys can be used to make open software players that can spread all over the net and be employed by everyone and anyone who cracks the cipher text can upload the unscrambled version to a peer-to-peer network obviating the need to even download a cracked player. Now, the law pretends that this is not true. It presumes that technological countermeasures to prevent copying are effective and treats investigating them and publishing their flaws is the equivalent of distributing housebreaking tools. Is it scientifically possible to prevent copying of a digital document? The answer is no. It is junk science. These systems do not work and cannot work. Businesses that rely on restricting copying have pitched their tents on the side of an active volcano. Governments should be urging them to evacuate to safer territory, not deploying mad, ineffectual laws to stop the lava flow.

Mike Hopkin: Cory Doctorow on the Podium. That is it from us. As ever, we play out with a sound of science. This week: Stephen M. Stahl of the Neuroscience Education Institute in Carlsbad, California.

Kerri Smith: Indeed, Stephen has devised this fantastic Gilbert & Sullivan-inspired ode to those who study drugs and their effects called 'I am the very model of a psycho pharmacologist'. I am Kerri Smith.

Mike Hopkin: And I am the very model of Mike Hopkin. Thanks for listening.

[Sound of Science]

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