Nature Podcast

This is a transcript of the 31st July 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 podcast@nature.com.

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Adam Rutherford: This week on the Nature Podcast:

Tony Freeth: The Antikythera mechanism would be remarkable even if it was a less clever thing than it is because there are so little like it physically preserved and even described in ancient books.

Adam Rutherford: Stunning new work on this 2000-year-old computer.

Charlotte Stoddart: We also take a look at the genetics of a complex disease.

Kari Stefansson: By figuring out the mechanism of schizophrenia I think it is possible that we will finally get an insight into how the brain generates thought and emotions.

Adam Rutherford: And we get our teeth into the origins of snake fangs with the scientist for whom getting bitten is just another day at the office.

Freek J. Vonk: I have been bitten a lot of times, but always by non-venomous snakes and I try to keep it that way.

Charlotte Stoddart: Freek Vonk coming up later.

Charlotte Stoddart: This is the Nature Podcast, I'm Charlotte Stoddart.

Adam Rutherford: And I'm Adam Rutherford. Next week is the opening of the Olympic Games in Beijing, but we are heading back 2000 years to revisit a device that was used amongst other things to record the dates of the ancient Olympiads. Long-time listeners of the pod may recall our feature in 2006 on an ancient Greek astronomical device re-discovered at the turn of the 19th Century. The first studies of the Antikythera mechanism revealed it to be a stunningly complex mechanical computer. This week in Nature, a team has delved deeper into the mechanics of the device which was pulled out of the ocean alongside some rich bootie. Nature 454, 614–617 (31 July 2008)

Tony Freeth: The first diver to come to the surface said he found a heap of dead naked people underwater. Second diver came up with a larger than life bronze arm and what they had in fact discovered was the wreck of a Roman merchant vessel stuffed full of Greek treasure and all this treasure was taken to the National Archaeological Museum in Athens including a small lump just over 30 cm high completely disregarded at that time. It lay in the museum for some months according to accounts and then it split apart.

Adam Rutherford: That's Tony Freeth lead author on the Nature paper.

Tony Freeth: And when it split apart, the curator noticed the remnants of some small precision gear wheels.

Adam Rutherford: In the middle of the 20th Century, a British physicist called Derek de Solla Price had the idea of using X-rays to look closely at the mechanism.

Tony Freeth: From these X-rays Price developed a model of how the mechanism works. It incorporated one feature, an ancient cycle of the Sun and Moon called the Metonic cycle which was absolutely critical to later understandings; one of the basic keys for understanding how the mechanism works. He also identified in the mechanism some epicyclical gearing that is to say gears that move with their axis moving on other gears; a completely astonishing revelation for ancient Greece.

Adam Rutherford: And Tony Freeth and his team continued the X-ray investigation, but this time using 21st Century technology.

Tony Freeth: We wanted 3-D X-ray information at high resolution and a world-leading company called X-Tek Systems came with a team led by Roger Hadland. They brought an eight-ton X-ray machine to Athens and they produced brilliant data. We have absolutely extraordinary high-resolution data of all 82 fragments of the mechanism and this has been really the basis of many of our revelations.

Adam Rutherford: Understanding the mechanics of the Antikythera mechanism is only part of the process of unlocking its function. Alexander Jones is a Historian of Ancient Astronomy at the institute for the study of the Ancient World in New York. He looked at the inscriptions that were being revealed by the X-ray work.

Alexander Jones: I heard of the research and I was invited to the conference in Athens where the new results were presented publicly and they were quite dazzling really, not only was there a clear consensus of how the gear working mechanism worked for the first time, but also there was the new evidence of a lot of new text inscribed on the surfaces inside fragments, on the outside surfaces of fragments. We knew there was text, but much more was being read and it was clear that there was going to be much more work to be done there. This was very exciting. The process by which we read the month names on the Metonic dial was very much back and forth between Tony Freeth and myself. He would send me by e-mail images that were made by his tomography software and these would be like very, very thin slices made through a fragment of the mechanism.

Tony Freeth: And we had a really exiting exchange of e-mails where I was giving him new information about bits of text I had read and he was doing the reverse. And I being completely ignorant of ancient Greek Astronomy couldn't interpret this, but Alex was the ideal person to actually interpret and understand what we were reading.

Adam Rutherford: Enabled by the new 3-D X-rays, the analysis of the inscriptions reveals information about the origin of the Antikythera mechanism. Many of the inscriptions form the months of a calendar that is associated with Western ancient Greece, including the once great city of Syracuse, which was the home of Archimedes, although it's tempting to think that he might have made the device, the timing just doesn't add up.

Tony Freeth: Archimedes was killed in siege of Syracuse in 212 BC, we think the earliest this mechanism could be, is a 140 BC, so we don't think Archimedes made the mechanism.

Alexander Jones: But there is a possibility if it came from Syracuse that it was made as part of a workshop tradition it goes back to the great old man.

Adam Rutherford: So what did they actually do? The new data have revealed at least two previously unknown calendar functions, as Tony Freeth explains.

Tony Freeth: Another thing we discovered was that the machine is an eclipse prediction machine. It has a dial which follows this ancient eclipse prediction cycle called the Saros cycle, if you have an eclipse in one month and you look 223 months later, you'll get a very similar eclipse whether it's of the Sun or the Moon and this repeat goes on for 12 or 15 Centuries. It's a remarkable cycle.

Adam Rutherford: And then there is the Olympic revelation provided by another small dial.

Alexander Jones: The Olympiad dial was a very exciting part of our work. A four year cycle is a bit of a surprise on the mechanism, because it doesn't really have an astronomical function. It has a cultural function. It was the timing for the games that the Greek cities organized in major cult centres at four year or two year intervals like the Olympic Games, which are not events of any scientific significance, but they were events that were of enormous social significance in the Greek world.

Adam Rutherford: The new study has revealed a truly remarkable feat of astronomical engineering, Tony Freeth again.

Tony Freeth: We've a complicated model doing complicated and extremely sophisticated things in a design which is pure genius.

Alexander Jones: It is fully at the top level of what we know that ancient Greek Science could do and ancient mechanical technology could do.

Tony Freeth: I sit for days looking at these X-rays and I find these tiny little clues about high works and what it did and I am still astonished by it.

Adam Rutherford: Alexander Jones and before him Tony Freeth on the Antikythera mechanism. They are beautiful papers available for free on our web site and you can see there are some videos showing reconstructions and animations of the mechanism, they are both at http://www.nature.com/nature and look out for a book on the mechanism by former Nature News Editor Jo Marchant that's called Decoding the Heavens and it's out in November.

Jingle

Charlotte Stoddart: No Kerri this week, she's on vacation, but before she left, she hunted down some very mini molecules.

Kerri Smith: Tiny pieces of RNA, aptly called micro RNAs are known to regulate gene and protein expression, but parts of this process like how they tweak the translation of genes into proteins is not well understood. Two papers this week from teams led by Matthias Selbach at the Max Delbruck Centre in Germany and David Bartel at MIT's Whitehead Institute address this question. I spoke to reporter Erika Check Hayden who has written a new story this week about the two articles. I started by asking her, what micro RNAs actually are, and how they fit into the bigger RNA picture. Published online 30 July 2008 Nature 454, 562 (2008) ; Nature advance online publication (30 July 2008) ; Nature advance online publication (30 July 2008)

Erika Check Hayden: So micro RNAs are part of this kind of RNA revolution that is sweeping through biology in which biologists are getting more and more excited about all the things that different kinds of RNA can do.

Kerri Smith: And they sort of regulate gene expression, is that right, that's their general function?

Erika Check Hayden: That's exactly what they do, they are gene regulators. So the classical paradigm of gene expression is you have a gene that is spelled out in DNA and it's transcribed into a piece of messenger RNA and that is translated into protein. So what the micro RNAs do is first they can attack the messenger RNA and chew it up so that they can't make anymore protein and that's been shown fairly well in experiments. What hadn't been as well studied was the step where the micro RNAs directly attack translation.

Kerri Smith: So it's been tricky then to get a handle on how much of an effect they actually have on protein levels because we don't really know exactly what they're doing in that stage. How have those two teams gone about tackling this problem?

Erika Check Hayden: So both of these teams used a version of mass spectrometry and what they did was they over expressed a micro RNA in its cell line. Then they grew these cells on a medium that contain heavy isotopes of carbon. So carbon that looks to the mass spectrometer different from the normal carbon that cells usually have. So when they grew these cells with over-expressed micro RNAs they could measure the effect of proteins that were newly made after the micro RNA was over expressed and they could compare the levels of these proteins to the levels of proteins in cells where micro RNAs hadn't been over-expressed and get a difference of the way the micro RNAs has affected overall protein expression in thousands of proteins.

Kerri Smith: What were they expecting to find when they did this and what did they actually discover, did it line up with what they predicted.

Erika Check Hayden: It's kind of an interesting question, so studies on the messenger RNAs had shown that a single micro RNA could affect hundreds of messenger RNAs. So I think they had may be expected that they would also see this when they took the proteins. I think may be what they didn't quite expect was how subtle those effects would be. These micro RNAs the team has found, they appear to act in very subtle ways changing the level of proteins between one and two folds may be three fold or four fold which is different from a lot of biological regulators that we know that can really ramp up the level of proteins like 10 or 12 times. One of the scientists who did the work called it a very beautiful finding because you know if you think about what's happening if you have all these micro RNAs, they can all affect hundreds of proteins at these various subtle levels, you will get these complex sort of overlapping patterns of protein expression that can be effected by these micro RNAs and you know for him he certainly gave them his appreciation that the biological systems are so robust that if one part of it fails then another part can sort of fill in the gaps.

Kerri Smith: What might this mean then, because it has been talk of using micro RNAs as drugs, to sort of tweak gene regulation where it's gone awry or in other situations like that? What might be the implications be of this finding for those kinds of therapies?

Erika Check Hayden: That's kind of a good news-bad news story depends, I guess, on how you look at it. So one thing we didn't talk about yet is that there have been a lot of scientists trying to write computer programs that predict which proteins the micro RNAs will interact with. Until now nobody had known whether those computer predictions really did ultimately predict the levels of proteins synthesis. So the studies had some good news about that which was that some of these computer algorithms actually do work pretty well. So that's kind of a good thing and you know scientists will be able to go back and look through this data and use it to find it too in those predictions. So you know ultimately that will allow people to have better knowledge of what these micro RNAs do before they go and test some in the clinic. Of course, the downside may be is that we'll have to be extremely cautious because micro RNAs we now know can interact with so many different proteins can have such fatal effects. They are not going to be most likely single target drugs, of course one of the teams pointed out that some of the, you know, for instance cancer therapies kinase inhibitors that we use in the clinic now, some of the best ones of those are also these "dirty drugs" that interact with a lot of target cells. So these are this kind of hopeful thing. Well they may not have a single target, but may be that means they'll be even more effective drugs than we had thought.

Adam Rutherford: Erika Hayden Check talking to Kerri.

Jingle

Charlotte Stoddart: Schizophrenia is a severe and complex mental disorder and scientists are still puzzling over the contributions of genetics, environment, neurobiology and psychology. Two papers in this week's Nature give further insight into the genetics of the condition. The team's from deCODE in Iceland and the International Schizophrenia Consortium surveyed the genomes of thousands of individuals and found three rare deletions, which significantly increase a person's risk of schizophrenia. One of these confirms a deletion found in smaller scale studies and the other two are new to scientists. I called deCODE's founder and CEO Kari Stefansson to find out more. Nature advance online publication (30 July 2008) ; Nature advance online publication (30 July 2008)

Kari Stefansson: What we are reporting are associations between deletions of large regions of the genome with risk of schizophrenia and actually these are fairly rare deletions and they confer quite a significant risk of schizophrenia.

Charlotte Stoddart: And you found these three deletions by searching for Copy Number Variants or CNVs, what are they?

Kari Stefansson: These are just segments of the genome that are duplicated so in some individuals you find one copy and in another individual you find two copies or even three copies and then in this instance what our findings is that that is part of this duplicated segment that is missing.

Charlotte Stoddart: I see, so could you explain what exactly you did to identify these deletions?

Kari Stefansson: So what we used to do that is parents and the children, we looked at trio parents and one child and we can also use duos where we have one parent and an offspring and we used a fairly large number of trios and duos to find these variants and then once we have found the we can start to look for association between them and the cases of schizophrenia.

Charlotte Stoddart: And in your study you find 66 variants and three of these, the three large deletions, showed strong association with schizophrenia. What can we learn then from this about schizophrenia?

Kari Stefansson: All of these deletions happen to have within them, genes that make proteins that they could easily make a significant contribution to disease mechanism. So they give us a foothold, they give us a little bit of an insight into what may actually be the biological or biochemical mechanism.

Charlotte Stoddart: How can we use this information then? Will it help us for example to develop genetic tests to identify people at risk of schizophrenia?

Kari Stefansson: You know one of these deletions from chromosome 1 account for 0.2% of cases, so these are rare variants. However, the risk conferred by these rare variants is fairly high that one-on chromosome 1, increases risk by 15 folds. So these are variants that confer very, very significant risk but they are so rare that they are probably not going to lead to development of meaningful clinical instruments. We have to collect more of these before we can even propose to go to gather any genetic tests.

Charlotte Stoddart: And do you have plans then to look for more of these genetic markets for schizophrenia?

Kari Stefansson: We have a very energetic team of people and we are collaborating with other very energetic teams all over the world, looking for more variants in schizophrenia. I mean schizophrenia is absolutely horrendous disease and it's is a very human disease. Remember that schizophrenia is the disease of the brain or kind of content to consciousness. It's a disease of thought and emotions. So I think that apart from clinical point of view and from the point of view how we develop an understanding of who we are, that is a terribly important task.

Charlotte Stoddart: Indeed and this work on schizophrenia is part of a much larger project at deCODE, you are using techniques to mine whole genomes of lots of individuals for genetic markers of many different diseases. So I wonder if you could give us a hint of what's next.

Kari Stefansson: First of all, as I was hinting at before, the brain is the organ that defines us as species and defines us as individuals. It is the working of all kinds of thought and emotions. So it is terribly important for us I think to figure out how the brain generates or how can the brain generates emotions and one way to feature that out is to study the diseases that affect the thought and emotions. So we have a large number of projects where we're trying to figure out what in our genomes dictates the population variants in cognitive function. We have a project on Alzheimer's disease, on Parkinson's disease, on Autism and a very large number of diseases of the brain and we hope that we will make a little bit of a contribution to the understanding of how the brain executes its normal function and how it is affected by these diseases.

Charlotte Stoddart: Kari Stefansson, founder and CEO of deCODE Genetics.

Adam Rutherford: Next up Geoff Brumfiel investigates lake like features on Saturn's biggest Moon.

Geoff Brumfiel: Titan is one of most interesting places in the solar system. That's because it has liquids on its surface, not liquid water, it's too cold for that, but lakes of liquid hydrocarbons like methane and ethane. Now the Cassini spacecraft which orbits Saturn and its moons has identified a giant lake of liquid ethane on Titan. Planetary scientist Robert Brown normally works at the University of Arizona, but he happened to be in London this week for a conference. I caught up with him to learn more. Nature 454, 607–610 (31 July 2008)

Robert H. Brown: It is a unique moon in the Solar System in that it is the only Moon that has a very thick atmosphere and it also has methane as a minority compound where methane plays the role in Titan's atmosphere that water vapour plays in the Earth's atmosphere. And the reason why methane is a liquid there is that Titan is much, much colder than here. So natural gas which is methane liquefies in Titan's atmosphere and forms raindrops made out of liquid methane and those raindrops rain out of the sky on Titan and they carve things like Gullies, Erosional Valleys and show us a whole much of landforms that are very, very similar to the Earth and so in pure planetary science stance, studying an object which is a Moon of a planet, but which in many other ways could be a planet in its own right is a very interesting thing.

Geoff Brumfiel: So you have found definitive evidence of what appears to be a lake on Titan, is that right?

Robert H. Brown: That's right we've been suspicious that there are lake-like features on Titan for a long time because there's an instrument on Cassini which is a radar instrument. It behaves as a large flashlight that illuminates the surface and it allows us to see the surface geology and so one of the problems up to now is that features that we've seen on Titan that look very smooth in the radar and have very similar features, very similar shapes and other characteristics to lakes on Earth looks smooth to the radar but there is no way to be certain that what we're actually looking at is a liquid. So in order to do that what you need to do is to look at Titan in wavelengths that are very, very much smaller, so that you can not only determine how smooth the surface is that you're looking at but you can also determine the composition. So there are two key things that we did. The first thing that we're able to do was to definitively determine the chemical ethane is there in a feature that is what we would describe as lake-like.

Geoff Brumfiel: So what does this lake look like?

Robert H. Brown: Well it's named Ontario Lacus because it is similar in size to Lake Ontario in the US, but to me it looks like a big footprint, in fact if I had to name it, I would have called it Big Foot Lake.

Geoff Brumfiel: And what would it look like if you're standing on the shore. I mean how would it be different than a lake on Earth?

Robert H. Brown: Besides the fact that you would freeze to death instantly if you stood on the shore, it would have features very similar to lakes on Earth. You would look down and you would see a liquid. You would see the kinds of things you expect for a liquid, where a liquid has a shimmering surface when the sunlight reflects off the surface. You would see those kinds of things. The difference is that you would be staring at a cryogenic liquid which is basically liquefied natural gas. So it's something that exists at about 90 degrees Kelvin above absolute zero or basically -180 degree C.

Geoff Brumfiel: And what are the next steps for studying this sort of hydrology of Titan, studying liquids on the Moon surface?

Robert H. Brown: Well one of the things that we want to do is to look out how these lakes evolve over time for seeing the effects of evaporation and the lake that we looked at in Titan's South Polar regions, we literally see a shelf or a beach or a structure which looks like an area that used to be covered with liquid and the lake has evaporated somewhat, so we want to study what happens to these lakes in a seasonal sense. We think, what we are seeing is that the lakes fill up in the winter time and when the summer comes around in the polar region, they start to evaporate and in some cases they will evaporate entirely, but I think even more important than that these lakes have sediments like any lake that you would expect and those sediments are composed of all kinds of things; but one of the things that we think occurs in these lake sediments is that they preserve a record of past changes in climate on Titan and past changes in its atmosphere and for me personally, I would look forward to the day when we can go back to Titan, land there with something that would literally dig down through the sediments or even be a lake submarine so that we can piece together what's happened to Titan over the 4-1/2 billion years that it has been around in the Solar System.

Charlotte Stoddart: Robert Brown from the University of Arizona talking to Geoff.

Adam Rutherford: Now it's generally a good rule to do your best to avoid snakebites. For Freek Vonk from the University of Leiden in the Netherlands, it's not an option. He is the lead author on a paper in this week's issue, in which he gets his teeth into the evolutionary origin of venomous fangs. I spoke to Freek and asked him about the different types of fangs that snake species brandish. Nature 454, 630–633 (31 July 2008)

Freek J. Vonk: Well, a few group of front-fanged snakes including the cobras and the vipers which are the most famous ones and they have their fangs in front of their jaw, so more or less like the position of our canine teeth and then other than that we also have a large group of snakes which have rear fangs dentition, which means that the fangs are located more or less at the position of our wisdom teeth and one of biggest questions in evolutionary biology was, are those fangs evolutionary related or not.

Adam Rutherford: You've resolved that question. Explain to us what you have done and what sonic hedgehog has got to do with snake fangs.

Freek J. Vonk: Yeah the sonic hedgehog first of all is a gene that is highly expressed and involved in the formation of dentition. So what we did was to solve this question, we turned to the embryonic development and we looked at the expression of the sonic hedgehog gene and first of all what we found was that within the front fanged snakes, so where the fang ends up in the front of the upper jaw in the adult animal and the fang actually develops from the rear part of the upper jaw and then it is displaced forward by rapid growth of the upper jaw of one part relative to the other.

Adam Rutherford: So you have shown that in fact these teeth once the fangs at the front and the fangs at the back are actually derived from the same evolutionary precursor.

Freek J. Vonk: Exactly, so what we also showed was that the rear fanged snakes there the fangs develop from its own developmental tissue. So if you compare it with our own dentition, each quadrant of our upper and lower jaw develops from one tooth forming tissue. So in the rear-fanged snakes it is as if our wisdom teeth would develop from their own tooth-forming tissue and other than that we showed remarkable similarity in developments between these rear-fanged tissue and the front-fanged snakes and if we map that over the evolutionary tree, we see that the most parsimonious explanation would be that those fangs are all derived from a rear fanged ancestor.

Adam Rutherford: And how does the association with fangs and venom, how is that evolved over the years?

Freek J. Vonk: Well first of all venom glands are older than the snakes themselves that is what we showed two years ago in Nature as well, the venom glands are about 200 million years old. They evolved in the lizard ancestors of modern snakes. But they were still quite small at that time, small and primitive what we call incipient venom glands. As soon as the advanced snakes evolved, the venom glands in the lower jaw, because they had both got lost and they modified, evolved the venom glands in the upper jaw to a very large and sophisticated venom gland in association with the teeth.

Adam Rutherford: Okay, so now snakes are not your run-of-the mill model organism, I have worked on fruit-flies and mice in my time. How do you actually go about performing this type of experiments on snakes?

Freek J. Vonk: Well first of all the fact that snakes are not a model organism is actually a good thing for me, because we can consider snakes as a sort of experiment form by evolution, because all the model organisms like mice, chickens, and of course fruit flies, they have been investigated extensively, but snakes has a totally different morphology with elongated bodies, fangs, venom glands, etc., so studying these animals can give us a broader knowledge of what evolution can do.

Adam Rutherford: Okay now I have had a quick look at your web site and you don't appear to be in the slightest bit afraid of snakes, whatsoever, where do you get your specimens from?

Freek J. Vonk: Well first of all I have a lot of friends also in Netherlands who keep snakes and they are very happy to provide me with eggs and I bred some snakes myself as well.

Adam Rutherford: And what about getting snakes from the wild?

Freek J. Vonk: Well you know I've been thinking about it, but if I have to be decide whether I want to get my eggs from captive specimens or from wild specimens I definitely choose for the captive specimens. I was in Indonesia at the beginning of this year and I caught a king cobra there which is the longest venomous snake in the world. And we found this king cobra we also found her nest and well about 20 eggs in there and no way would I ever have been able to take only one egg with me, because it was just too beautiful to see in the wild.

Adam Rutherford: So you prefer working with snakes in the lab or in the wild?

Freek J. Vonk: That's a very, very difficult question for me. I think I have to say both. I want to work in the lab because of course that's where most discoveries are made but I also absolutely love being in the field to find the snakes in their natural habitat, both of the things are just what I would like to keep on doing for the upcoming few years.

Adam Rutherford: And Freek have you ever been bitten?

Freek J. Vonk: I've been bitten a lot of times, but always by non-venomous snakes and I try to keep it that way. I have had some very, very close encounters with venomous snakes, but I usually try to be very careful because a bite by a venomous snake, it is not very good.

Adam Rutherford: Well quite. Freek Vonk boldly going where, Indiana Jones fails to tread. You can see some rather cool pictures of Freek wrestling with some pretty scary looking snakes at his website that's http://www.slangengif.nl. Slangen is the Dutch for snake, just in case if you're wondering.

Charlotte Stoddart: That's it from us. Tune in next week when we'll be looking at the lopsided Earth, delving into the X-files and featuring the winner of the PODium competition we ran earlier in the year. This is the Nature Podcast, I'm Charlotte Stoddart.

Adam Rutherford: And I'm Adam Rutherford, watch out for those snakes.

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