Nature Podcast

This is a transcript of the 17th October 2013 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.

Kerri Smith: This week comparing across cancers could help us understand them better.

Magdalena Skipper: Thinking about cancer types as equivalent to different species helps us understand how cancers originate, how they progress to help us treat them.

Kerri Smith: And does a high impact paper really change a scientist's life?

Stephen Curry: Nature and Science get things wrong from time to time every so often they pick a turkey or they publish something that turns out to be manifestly poor science.

Kerri Smith: Plus we piece together the nervous system of an ancient arthropod. This is the Nature Podcast for the 17th of October 2013. I'm Kerri Smith.

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Kerri Smith: No two cancers are the same. That much became clear to scientists as soon as they started work on the genomes of cells from different cancer types. There's a list of mutations that can increase someone's likelihood of breast cancer for example and scientists know a lot about how tobacco smoking mutates genes in the lung. But is there anything that all cancers have in common? And if so, could scientists use knowledge of these common themes to treat or prevent multiple cancer types? Finding out is one of the goals of The Cancer Genome Atlas project. They published a suite of papers this week including one in Nature and a few more in Nature Genetics. Nature's Genetics and Genomics Editor Magdalena Skipper joins me in the studio to unpack the new results. First Magdalena what's been the run up to these findings. Nature 502, 333–339 (17 October 2013); Nature 502, 306–307 (17 October 2013)

Magdalena Skipper: Until recently most studies have focused on individual cancer types, the Cancer Genome Atlas Consortium themselves have published a number of impressive papers, each of which focused on an individual cancer but then looked beyond the genome to look at the transcriptome - so what types of genes were transcribed and expressed in a given cancer type. They have looked at epigenetic modifications to understand the layers that are superimposed on top of the genome in each individual cancer. But now armed with so much data, they have decided to launch a pan-cancer initiative and so the principle here is to apply really quite well established principles of comparative genomics. So take those datasets from individual cancers and compare them across cancer types.

Kerri Smith: You say comparative genomics; Nature in the past has published lots of this stuff. So human versus gorilla versus chimp genomes and here we have essentially different species of cancer genome being compared.

Magdalena Skipper: Exactly. This comparison, thinking about cancer types as equivalent to different species and using principles of evolutionary biology and population biology or evolutionary genetics and population genetics is actually an emerging theme in cancer biology which helps us understand how cancers originate, how they progress to help us treat them.

Kerri Smith: Now this is a way of looking at as you said multiple cancer types. What themes do seem to be emerging when people are comparing all these different species of cancer?

Magdalena Skipper: In this particular effort, the Pan-Cancer Consortium have looked at 12 different cancers and so for example in the Nature paper by Li Ding and Colleagues, the authors have looked at point mutations and small insertion- deletions that affect only a couple of nucleotides at a time and certain themes come out from that investigation such as for example, they are able to identify around 130 significantly mutated genes which affect tumour biology but now right across different tumour types. So, just the reminder then that now we're not looking at a single cancer but all different cancer types.

Kerri Smith: And some of these presumably are not surprising because they're genes that we already know to be implicated in multiple cancers. The gene p53, I suppose comes up as one of those 130 odd.

Magdalena Skipper: That's right, but there are some other interesting insights in terms of biology. For example, we've been getting hints from previous analyses, individual cancer analyses that mutations in genes that affect chromatin play an important role in cancer and indeed this is something that is emerging very strongly as a theme from this pan-cancer comparison.

Kerri Smith: So, just remind us what chromatin is?

Magdalena Skipper: So, chromatin is the assemblage of DNA and proteins that around which this DNA is wrapped up. So it's the structure within the nucleus in which DNA is contained.

Kerri Smith: So, mutations have been found then in this study by Ding et al in chromatin and in lots of other cancer genes that were not as surprising but in a different paper that's quite complementary in Nature Genetics, a different team looked at the sort of structure of the genome and mutations that have to do with that.

Magdalena Skipper: That's right, so there the team led by Rameen Beroukhim looked at structural variance in the genome. Whole genome duplications, big structural rearrangements and they find as many as 37% of tumour types carry whole genome duplications. That's actually quite a striking number something we did not appreciate before.

Kerri Smith: Now it's not just the pan-cancer team, The Cancer Genome Atlas team doing this kind of comparative effort, a team led by Mike Stratton at the Sanger Centre in Cambridge have also been comparing different cancers and how have they done it? How is their approach complementary?

Magdalena Skipper: Their approach has been to take 7000 cancers of 30 different classes and look at mutation signatures and what these mutation signatures are going to tell us is they're going to tell us about the biological processes that creates these mutations and thereby leads to carcinogenesis and tumour development. So, for example, we already know that certain carcinogens in tobacco cause particular mutational signatures in the lung and similarly UV causes very particular signatures in the skin when you look at melanoma. What Stratton and colleagues have done is identify new signatures; some of them are associated for example with age or diagnosis. Others are associated with defects in DNA repair.

Kerri Smith: Eventually are there ways in which knowledge like this could help us treat cancers better, even prevent them?

Magdalena Skipper: Absolutely. Amongst the findings are clear cut potential targets for therapy. Therapy which, on one hand, might be restricted to individual cancers but some of these results that come out from pan-cancer analysis actually point to specific processes that can be targeted across different cancer types. Similarly for example in the Nature paper by Ding and colleagues what really emerges right across the different cancers is that knowing the clonal architecture, so how different subsets within a tumour develop and accumulate mutations can help or should help devise sort of tailor-made treatment for individual patients.

Kerri Smith: Okay. Magdalena Skipper thank you so much for coming in. Those papers can be found, the Ding paper, on the Nature website http://www.nature.com/nature as is the Stratton paper we mentioned and a collection of other papers http://www.nature.com/ng for Nature Genetics.

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Kerri Smith: Still to come in the research highlights, a factory popping out pills with ease and freezing cold turtles. But first, to understand the diversity of modern life, scientists have long delved into the fossil record. One of the most diverse groups of creatures is the arthropods, the lineage which includes insects, crustaceans and all manner of other creepy crawlies. Recently our understanding of these creature's early evolution is being advanced by an area we could call neuropalaeontology, that is the study of ancient nervous systems. Noah Baker has been finding out more. Nature 502, 364–367 (17 October 2013)

Noah Baker: Some of the oldest known arthropod fossils come from the Cambrian period over 500 million years ago. Xiaoya Ma from the Natural History Museum in London has been looking at fossils like this from a particularly special site in China.

Xiaoya Ma: I am looking at these fossil materials from South West of China, one of the oldest fossil assemblages in the world, then they have a huge amount of like a different diversity group of animals. They also have very exceptional soft body preservation. They are quite world famous.

Noah Baker: These Chinese rocks have turned out some amazing finds. Last year on the podcast we heard from Greg Edgecombe who worked with Xiaoya on a species found in these rocks called Fuxianhuia.

Gregory Edgecombe: Well, what we were working on here is an exceptionally preserved arthropod from very early in the fossil record of animals and the fossil we're working with here is something that you almost never get in fossils of this age and this is the preservation of neural tissue. We're seeing the outline of the brain in one particularly fine specimen and we're seeing some of the neural tissue inside the eyes as well.

Noah Baker: Now Greg and Xiaoya have turned their attention to another fossil from the same rocks. A species from a now extinct group, the great appendage arthropods.

Xiaoya Ma: Great appendage arthropods are a group of extinct arthropods from the Cambrian rocks. So, they can be found in China, in Canada, in Australia, but all first the name's really deriving from their first pair of head appendage which is comparably much larger than the other appendages of the animal.

Noah Baker: The new specimen is called Alalcomenaeus and again the team are interested in its nervous system. One year on from the description of Fuxianhuia and the team are using techniques not that dissimilar from modern brain scanners.

Xiaoya Ma: This particular specimen we're studying, we're using some very new imaging technique almost like x-ray scanning like medical CAT scan almost and it revealed some detailed structure as a three-dimensional information and all this information get together, help us restore the whole central nervous system of this animal and this is the most complete central nervous system we know from any animals from the Cambrian period. This information helps us to resolve this animals' phylogenetic relationship.

Noah Baker: Where Alalcomenaeus and other great appendage arthropods fit into the evolutionary tree has been up for some debate. There are two main groups: The Mandibulata - insects and crustaceans and the Chelicerates - Spiders, Scorpions and Horse Shoe crabs. The brain of Fuxianhuia indicates that it sits somewhere in the Mandibulata.

Gregory Edgecombe: The brain of Fuxianhuia appears to correspond to what we thought was the more derived or advanced condition as we see in insects or crustaceans.

Noah Baker: But until now scientists couldn't agree where to put great appendage arthropods like Alalcomenaeus. Some thought they were early Chelicerates and now the neural structures suggest they were right.

Xiaoya Ma: Because we didn't know the neural structure of both of these sorts of fossil arthropods before, so many palaeontologists working on their external morphology like appendages already proposed the great appendage are related to the Chelicerate. Our research provides entire novel data to backup this idea and to settle any controversies.

Noah Baker: Neural structures of both Fuxianhuia and Alalcomenaeus have provided a unique window into arthropod evolution.

Xiaoya Ma: Arthropods is certainly the largest phyla in animal kingdom. They have amazing diversity but those diversity also gave us a lot of difficulty in terms to understand their early evolution because these appendages can be highly more defined. The central nervous system is relatively stable through the evolutionary history. So that's why it also makes it very important to understand their central nervous system. Until very recently we know almost nothing about the neural tissues from the fossil material and through this very, very exceptional preserved fossils, they actually show us the neural information but not only generally neural information, they actually show us very detailed information which we can do direct comparison with modern taxa.

Kerri Smith: Xiaoya Ma from the Natural History Museum in London ending that report from Noah. Now it's time for the research highlights read by Charlotte Stoddart.

Charlotte Stoddart: A new type of factory could speed up the production of drugs saving the pharmaceutical industry time and money. Instead of spreading manufacturing over several locations as normally happens, the new factory brings all parts of the process under one roof. Chemical building blocks flow in at one end, then the drug is made crystallized, dried, and coated in one continuous process far more efficient than the traditional start-stop method. The factory, the first of its kind produces a hypertension drug. You can read about in Angewandte Chemie International Edition. Nature 502, 274 (17 October 2013)Fresh water turtles can survive the winter at the bottom of frozen lakes despite a complete lack of oxygen. But they do not as some have suggested, fall into a coma. Researchers in Denmark submerged turtles in cold, oxygen depleted water to put them into false hibernation. Surprisingly the animals still responded to light and increased temperatures. This suggests that hibernating turtles are in a low energy but vigilant state. Read more in Biology Letters. Nature 502, 274 (17 October 2013)

Kerri Smith: Many labs have a bottle of bubbly on standby for when their research is accepted by a top tier journal, but apart from that extra glass of cava does a publication in Nature or Science really affect your life? Geoff Marsh has been finding out. Nature 502, 291–293 (17 October 2013)

Geoff Marsh: With journals like Nature and Science rejecting around 90% of their submissions, a publication in these premier titles perhaps unsurprisingly shines like a badge of honour on a scientists' CV. But are these publications unfairly weighted? Does where you publish matter more than what you publish and how much of problem is this? Stephen Curry, a structural biologist and enthusiastic blogger on such issues from Imperial College London joins me now. Good Morning Stephen.

Stephen Curry: Good Morning Geoff.

Geoff Marsh: Firstly then, as an active scientist yourself, what's been your experience with trying to publish in these top tier journals.

Stephen Curry: Well I think it's probably common with most people, I've had a go every now and then, but most times been knocked back without even the paper being sent out for review. I have published once in Nature but it was 20 years ago and it was on a paper where I was very much a middle ranking author, but I guess I knew as a young researcher back then that, you know, this was the game that I had to try and play if I wanted to get on in my career.

Geoff Marsh: And so for you what was the result of that publication, was it just more high-five's amongst your colleagues or were there any real benefits?

Stephen Curry: Well, you know, there's definitely a sense of kudos that comes from publishing in such a high ranking journal but I don't think in my case it was make or break for my career, does no harm. I was certainly glad to have that listed on my CV, but many of my other papers published around the same time were in more specialist journals and I still managed to get a job and I'm now working as a professor of structural biology at Imperial College, so you know it's not make or break.

Geoff Marsh: What do you see as the dangers of this bias towards crediting publications in these top tier journals?

Stephen Curry: One is that it slows down the publication process because there's a very narrow door getting into Nature and Science and so there's a very big queue lining up behind it and so 90% of the papers are rejected. But those 90% of papers mostly will be very, very good work and it will eventually get published but it just means that having to go through the process of knocking on Nature or Science's door first means that you introduce a delay and so it slows down the publication of science. It's also unfair because the threshold that Nature and Science operate - publishing 10%, that's entirely artificial. You know Nature and Science could easily publish probably 20-25% of the manuscripts that they receive and there would be no appreciable drop in quality. And yet it's only those that make it through the door that earn the credit, earn the badge of an impact factor from Nature or Science, but the ones that haven't made it or have just had the door closed on them, they probably are palpably going to suffer in their careers and that seems to me manifestly unfair.

Geoff Marsh: But isn't it right though that the most highly selective journals, I mean, we've heard that Science and Nature, a lot of them reject 90% of their submissions. Isn't it right that publication in one of these journals does deserve a bigger reward?

Stephen Curry: Well that presupposes that every paper that goes into Nature or Science is a big hitter, is a winner. But it simply isn't justifiable if you look at the numbers because many, many papers are published in Nature and Science that don't get very many citations or don't turn out to be the big game changer that they were thought to be when they were selected and sent out for review. So we have to acknowledge that you know Nature and Science get things wrong from time to time. Every so often they pick a turkey or they publish something that turns out to be manifestly poor science, you know, the arsenic life paper in Science, just to cite one of the more famous examples, a piece of nonsense that any undergraduate could have told you was nonsense was published and so the other thing to remember of course is that these general disciplinary journals, Nature and Science they're not just judging on the quality of science, they are also looking for topicality for news worthiness, you know is it sexy? These are also the criteria.

Geoff Marsh: And so are people just moaning about this or are there people taking action to sort of change the status quo.

Stephen Curry: Well, a lot of people are moaning, that's certainly true and I have moaned on my blog about it. But I think there is a lot of positive action coming out now. One of the positive things that's come out in recent months in fact is the declaration on research assessment which is an initiative that has come from a number of publishers and learned societies and it's specifically targeted at getting people, funders and universities to avoid using impact factors in their assessment and it recognizes that it has come to have undue influence in our business of hiring new faculty, of promoting them and of determining whether or not to fund their grants.

Geoff Marsh: So you've talked there about better ways to assess the value of a paper once it's been published. Do you see there being any change to where young scientists try to publish?

Stephen Curry: I think the rise of open access is creating new venues for people to publish in and many of these have turned out to be of, I think, surprisingly good quality. Overall the impact factor of PLoS is around four which is actually very respectable given the breadth and the size of the journal and I think that's taken a lot of people by surprise. A number of people I have met, I myself have done this in the past 12 months, who have published in PLoS One seem to be just rising and rising. They've published over 25,000 papers last year and I think that younger generational scientists, they've grown up with the internet, they've grown up with digital publication and they're much more friendly to it, but the trouble is, for them they still feel that well I still need to publish in a top tier journal if I want to make a success of it and it certainly would not be fair to expect the younger generation of scientists to carry all the risks of breaking away from our addiction to impact factors.

Kerri Smith: That was Imperial College's Stephen Curry talking to Geoff Marsh. And there's a feature on publishing in top tier journals in this week's magazine alongside a host of other articles on scientific impact. Check that out at http://www.nature.com/nature.

Kerri Smith: Finally this week, it's the news chat and Chief News Editor David Ray joins me in the studio. First up this week, the obvious topic, the shutdown of the US ongoing. Thursday of this week, the 17th is likely to be the day that they crossover into sort of budget default unless something happens. David what's the latest that you've got.

David Ray: Yeah as you said Kerri I mean this has been running on for about two weeks now. It looks like it could be coming to be a bit of a head finally. I think the American public will be more grateful for that than the scientists but the impact for scientists has been pretty massive and I think this week in our piece we analyse exactly, now that we know better what the fallout is, exactly how it's affecting them and one of our reporters went to the NIH labs in Bethesda in Maryland to have a look around there and see what was going on, were there any lights still left on and she found out that there weren't, to be honest. There was an absolute skeleton staff, most of whom were having to look after the cell lines and the live sort of organisms and the live lab tests that are going on and also a few sort of technicians and things about as well but ultimately you know a sort of ghost ship if you like and that is something that is being echoed in government labs across the states at the moment. The Antarctic, all the bases down there in serious jeopardy at the moment, 1500 scientists and technicians could well be called back which would mean essentially the entire Antarctic season is lost which would be a year's worth of data from penguin counting to climate change data loss and that's quite a sort of significant developing not just for the Americans but for the wider scientific community.

Kerri Smith: Yeah, so there were international effects of the US shutdown of course as you would expect. Looking forward, we don't know what's going to happen on Thursday of course. But what could be the future implications for science - there's obviously missing datasets already.

David Ray: The hangover is going to inevitably take a few days to weeks possibly to sort itself out and what happens after that is everyone is going to have start checking okay, what did we lose out on? Do we need to start commissioning new work to cover the gaps that the shutdown made? So I think there's going to be an all mighty picking up of pieces going on, once the US government does agree the new budget and science can get back on a level footing.

Kerri Smith: Are there hints of what the further future will be like? So obviously there's some tidying up to be done. There's this hangover as you said. But if we look past that to what the budget might say for science in the future, what's likely to be the outcome of that?

David Ray: Another good question. I think I mean the danger of the US system means that something like this of course can happen every year and has happened in the past as we've seen. So what will happen in the future? Will a science lobby sort of grow to ensure this doesn't happen next time or that they get some sort of exemption, it's an unlikely possibility but it's something that the science community will definitely be needing to think about and the impetus of all this lost work will be enough to drive them into doing something I'm sure.

Kerri Smith: All right, so the shutdown leading to dark times quite literally in the NIH labs that reporters have been visiting that story online of course accessible for free. Let's turn now to the other side of the pond to France and to the ITER experiment where construction has been delayed.

David Ray: Yeah, kind of echoes of the shutdown again here not quite the same kettle of fish but construction delays at ITER which is a huge fusion project, the idea is they can make energy, make electricity ideally out of fusion power and that's within a sort of about 15-year target they're looking at 2028 as the date that'll happen they think, so that they're aiming to get 10 times as much power out as they put in, a long way from that and construction delays have meant that the research which is a sort of step-by-step schedule to get to this main goal is out of kilter because of the delays. So they've had a meeting this week to discuss how they sort out their research program and what they've decided is they want to entirely focus on the goal of generating power and this means that a lot of research is going to be side-lined, some of the more sort of basic physics about research into fusion and other things that they can use this enormous Tokamak which is the fusion, you know, reactor they have. So they're trying to sell it as a kind of good news story and that we're still focused on getting to power generation but I think a lot of research is going to be certainly delayed if not passed over on the way to get there.

Kerri Smith: What's the nature of the delays? Is it just that they don't, you know, can't source enough construction workers, or they don't, have the science right to be able to build the equipment they need, what exactly is going on?

David Ray: Yeah, well I mean unfortunately I think they've been a victim of further cost cutting pretty much like everyone else has I think and it's run by the EU and about six other countries including China, Russia and France and all of those countries are suffering through economic losses. So cost cutting is happening at the forefront of science and the knock on consequences of that is that ITER can't put together its Tokamak and its fusion experiments as quickly as it would like to.

Kerri Smith: Right, the perils of giant projects and of course one of the most giant we've covered in the previous couple of weeks, the IPCC has just released its latest report and now a whole bunch of sociologists are going in to look at how exactly it's done that and what such a big organism, if you like, looks like on the inside.

David Ray: So how the monster works I think is the best way, so this is actually quite a really great story actually, the IPCC has had an application from a bunch of ethnographers, social scientists to study the actual individual members and how they work together. So it's not about the work they're doing, it's nothing about climate change, it's more about how so many people can come up with such a big report essentially which is you know possibly world changing. So these guys are going to go in. They're going to sort of watch them work together, how they talk, how they communicate, up to 200 members need to be involved in this. So do they have any biases, are those passed on, how are they counter weighted, you know, prejudices, simple is the right doing the right thing I suppose. So it's going to be quite fascinating to, a:) find out if the IPCC let them come in to do this and b:) if they actually find out anything interesting possibly post back into the system to say IPCC this is how you could be doing this 10 times better.

Kerri Smith: So, we don't know yet the outcomes of this because they haven't even had sign off for this project.

David Ray: Exactly yeah, it's an application at the moment but the IPCC are, I think the reason it's made into the news is that they're taking it quite seriously. So I think they appreciate that they could work better together, so why not I suppose. But it's obviously confidentiality issues and all manner of, you know, sort of privacy and security that the IPCC I am sure will not want people to get out but you know it looks like at the moment like they may well say yes.

Kerri Smith: Now David up until this point you've had your serious face on because we have not been talking about Jurassic Park. Well we're about to kind of do that a little bit because this week in the news a mosquito made it into the headlines that's been found with its blood meal also fossilized.

David Ray: Absolutely, in the actual film version I suppose the mosquito was in a big lump of amber. This isn't quite the case, it was found in sort of a shale fossil from Montana. It's 46 million years old. It's got a bona fide blood meal inside it which scientists have now sort of proved by finding some traces of iron and porphyrin, inside it, they don't know what animal it came from, most likely it was some sort of vertebrate. The team we found at the US National Museum of Natural History I think it's the oldest blood sucking animal yet found absolutely 46 million years, it's pretty old indeed. So it's an interesting find. I think that's the kind of first thing that they've been able to identify the blood inside it for the first time which is a kind of, it's been very hard to do. They suspected there was blood in it but they haven't' been able to prove until now.

Kerri Smith: But they're not thinking presumably of extracting this blood of this vertebrate whatever it was and turning it into a theme park.

David Ray: Alas, the DNA had completely degraded, so it was only traces of these molecules that they found as opposed to the actual DNA.

Kerri Smith: David Ray Thank you so much for coming in. More news available and more details on all of those stories at http://www.nature.com/news. That's it for this week. Join us next time when we'll be finding out the truth about the T-rex. I'm Kerri Smith. Thanks for listening.