Nature Podcast

This is a transcript of the 8th 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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Kerri Smith : Coming up, find out which comic and curious creature is the latest to have its genome sequenced.

Chris Ponting: This is a wonderfully weird and strange creature. It is not that the God has a fantastic sense of humour. It is just that we scientists cannot always second-guess what we're going to find in nature.

Adam Rutherford: The gene that maketh a man!

Robin Lovell-Badge: Sry confirms to one particular male stereotype. It is asleep during early development. It then wakes up for a few hours, just long enough to give out an order instructing Sox9 to do all the hard work.

Kerri Smith: And why slimming and staying slim can be so tough.

Kirsty L. Spalding: This data indicates that it could be quite difficult for people to keep the weight off since there is no possibility as our data shows for them to actually you know reduce the number of fat cells.

Kerri Smith: This is the Nature podcast. I'm Kerri Smith

Adam Rutherford: And I'm Adam Rutherford. To kick us off this week a creature so bizarre that when it was first reported museum curators thought it was a fake, a chimera stitched together from parts of other animals. Now we've published a fair few genomes over the years, but you'll do well to find one more weird than this. Yes, Australia's duck-billed platypus is the latest creature to join the genome club, those beasts who have had their entire genetic code sequenced. The platypus is most certainly a mammal, but many of its traits are not typically mammalian. Here is Jenny Graves from the Australian National University who is part of the sequencing team. Nature 453, 175–183 (8 May 2008

Jenny Graves: The platypus is beautifully adapted for its aquatic habitat. It's a lovely little creature. You can see that it is truly a mammal, it has fur and it feeds its young on milk. But it has a lot of reptilian characteristics, for instance, its eye structure is very much like a reptile and particularly its reproductive organs are like reptiles, so much so that it actually lays eggs.

Adam Rutherford: And unsurprisingly, the new study has revealed that its genome is a hybrid of mammal and reptile sequences, but it is not just this mixture of genes that makes its genome unique. Take for example sex determination, Nature's Senior Editor Chris Gunter explains.

Chris Gunter: When you look at, for example, humans, humans determine their sex chromosomes based on one X and one Y chromosome. When you look at the platypus for some strange reason they have 5 X chromosomes and 5 Y chromosomes and if you would look in a platypus cell, you would see that these form a chain all the way down by binding to each other and the sequences that determine sex are actually on the last X, but the sequences actually look like birds; they are not like mammals which is very strange.

Adam Rutherford: The platypus is a monotreme, a group of egg-laying mammals that form a lonely branch in the mammalian family tree with all other species veering off in a different direction. Its weird characteristics may be a product of evolving in isolation in Australia, since the break up of the super continent Pangaea more than a 150 million years ago. The genome sequence has now revealed that even some of the mammalian characteristics of the platypus are unusual. Chris Ponting was part of the sequencing effort.

Chris Ponting: One of the major findings we immediately saw is that it has a phenomenal range of receptors called vomeronasal receptors that is the largest that we have seen among any mammals. What we think that is, is that when the platypus dives under water foraging for food, it is able to appreciate a whole different types of chemical stimuli in its environment and the odd thing about the platypus is that it closes its eyes, it closes its nose whilst it dives and so all of the chemicals that will be seen by these receptors will enter through the back of its mouth in such a way as only previously been seen among creatures like the hippopotamus, another aquatic mammal.

Adam Rutherford: Right, so it has got reptilian genes a very peculiar and somewhat bird-like way of determining sex and a staggering set of chemical receptors to help forage for food while it swims with its eyes shut, but it does not end there, here's Chris Ponting again.

Chris Ponting: One of the extraordinary things about the platypus is that it has venomous spurs. The adult males are able to envenomate, they are able to inject venom from the ends of their spurs into unsuspecting biologists or any one else and apparently it's excruciatingly painful.

Chris Gunter: It is able to deliver a venom which can kill dogs and that can incapacitate humans for a number of weeks. It is so powerful and the genome shows that this venom looks like reptiles although it has evolved completely independently from reptiles. So it is just a fascinating and weird animal.

Adam Rutherford: That was Chris Gunter again. Strange though it is Jenny Graves says that sequencing the platypus genome is not just the genetic equivalent of a circus freak show.

Jenny Graves: Well for comparative genomics weird is good, we call it informative variation and we can use the differences and the similarities in sequence between a platypus and a human to search for genes. Not just platypus genes but also human genes and we can use that to search even for the little sequences that turn these genes on and off.

Chris Ponting: This genome sequences are incredibly important because it plugs the hole in our knowledge for mammalian evolution. Though we knew something about marsupials, we knew something about placental mammals, we knew something about the birds and so the platypus then provides the missing link between the lizards and the birds and ourselves the placental mammals. This is a wonderfully weird and strange creature. It is not that the God has a fantastic sense of humour it is just that we scientists cannot always second-guess what we are going to find in nature.

Kerri Smith: That was Chris Ponting from Oxford University ending that report. Unlike those studying platypus sex, researchers looking at sex determination in other mammals including humans have only one set of sex chromosome to play with. In another paper this week, the various genetic switches that lead an individual to end up male or female have been explored. Here's Mike Hopkin with more.

Michael Hopkin: Ask any geneticist and they will tell you that being male is a lifestyle choice whereas being female is the default option. In fact, it takes just a single gene on the Y chromosome to kick-start a host of other genes that help an embryo to grow up male. New research now shows how the gene called Sry interacts with other genetic factors to pull off this remarkable feat. I spoke to lead researcher Robin Lovell-Badge at the National institute for Medical Research in London and began by asking him about the character of this fundamentally male gene. Nature advance online publication (4 May 2008)

Robin Lovell-Badge: In essence some might think that Sry confirms to one particular male stereotype. It is asleep during any development even when the gonad cells begin to form. It then wakes up for a few hours just long enough to give out an order instructing Sox9 to do all the hard work. Sry then go backs to sleep, its job done and it stays asleep for rest of the development.

Michael Hopkin: This Sry gene given that it's promoting the activity of other genes and that's its job, what sorts of other genes is it activating and how does it set the cells off into developing into testicular cells.

Robin Lovell-Badge: So we and others have shown over the years that Sry must be acting within a particular population of cells in the early developing gonad that will in an ovary, in the absence of Sry give rise to follicle cells that surround the growing oocyte and in the testis these cells give rise to Sertoli cells that support and direct the germ cells to eventually make sperm. Moreover, it was shown that Sry acts very briefly. It is only on for a matter of a few hours for a cell, so it does not have long to do its job and for a number of reasons the best candidate for a gene to be regulated by Sry was a gene called Sox9 which is in the same family as Sry.

Michael Hopkin: So does that solve the riddle then of how something like Sry that is only activated for a few hours can make all these genetic changes that then set the cells off or is it a quite important developmental pathway.

Robin Lovell-Badge: Yes, but what was needed was to show that actually that there was a real link between Sry and Sox9 and so this was guessed but there was no evidence and it was a difficult problem to get to because Sox9 is not only active in the testis but it is also active in many other tissues in development and consequently it has a very large complicated regulatory region, which is over a mega base, over million base pairs long. So we have to first of all find a specific path of this very huge range of distribution that was giving expression of Sox9 specifically within developing testis. So that took actually quite a few years and many mice to find and to cut a very long story short, we find in that sequence of DNA there are well recognized binding sites for a number of transcription factors including a factor called steroidogenic factor 1. So essentially what we found is that SF1 is involved in the initiation of the activity of Sox9 and then the role of Sry is simply to work together with SF1 and to boost the level of Sox9 above a critical threshold.

Michael Hopkin: And I think that fits with our idea of how embryological development generally tends to proceed as female as a default position, unless a genetic switch is flicked and it becomes male if you like, but does your work have anything to say about cases where that process goes wrong so people might develop into what you might term the wrong sex for the chromosomes that they have.

Robin Lovell-Badge: It almost certainly does. So we know the Sox9 is critical so mutations in Sox9 lead to sex reversals, to give XY females but also we think that this particular regulatory region integrates not only all the signals required for normal male development, but also several that are required for female development, so we suspect that while in the initial event we need to do in making an ovary is to ensure that Sox9 goes off and stays off and so we suspect that there are genes in the female pathway that do that by interacting with this particular regulatory region.

Michael Hopkin: When this is all stuff that happens long before birth is fairly early in embryological development, so are there any potential practical applications, perhaps you know for treating people who might, you know, have turned out as we are calling it the wrong gender.

Robin Lovell-Badge: Not directly except for in terms of genetic diagnosis, so understanding, you know, what's gone wrong when you have someone born who is either completely sex reverse or cases of inter-sex development, so where they have characteristics of both male and females, understanding that simply with the genetic diagnosis is already important because clinicians will take a number of different routes to treating a patient depending on the nature of the gene that's defective.

Kerri Smith: Robin Lovell-Badge of the Medical Research Council in Mill Hill in London. Coming up shortly, we will be discovering how the legacy of the atom bombs of the 50s and 60s are helping researchers to study cell turnover in humans.

Adam Rutherford: But next up is geologist Chris Turney with the Podium.

Chris Turney: In an uncertain world, the past gives us the opportunity to reflect upon and learn from what has gone before. It's pretty clear we don't feel nice. The air we breathe contains a level of carbon dioxide not seen for at least 650 thousand years and may be for as long as 3 million years. Assuming the insatiable need to dump vast amounts of greenhouse gases into the atmosphere is taking our planet out of its comfort zone. The risks we face are written in the remnants of the past. Researchers have for many decades now been scrutinizing features preserved in trees, shells, mud and ice, to get the glimpse at climate past. What they have found is chastening. Climate can change far more abruptly than we might like to admit; a little more green house gas in the air, does not cause a little change in climate. Our planet is one set of feedback built in another; a bit of warming can cause a cascade of unintended consequences. We've an ever-warming planet. The earth's ability to soak up greenhouse gases is already lessening causing yet more warming. If it is one thing we can learn from what has gone before, is for that the world can change at a moment's notice. When we will reach the tipping point is anyone's guess, but we're getting close. We are now seeing changes that are without precedent for thousands of years. In 2002, a chunk of Antarctic peninsular ice known as a Larsen B-shelf collapsed into the Weddell Sea never to be seen again. This wasn't any old piece of ice. This was a piece of the size of Rhode Island and it wasn't something that happens every Tuesday week. It had been stable for 12,000 years. Other dramatic changes are also taking place. The Northwest Passage opened up in 2007 for the first time in what looks like 9000 years. Glaciers in the Andes and Europe are falling back to a size not seen for 5000 years. Meanwhile temperatures across the Northern Hemisphere of a high say, being for at least 1000 years. We know from 55 million years ago for putting large quantities of greenhouse gases into the air can lead to catastrophic warming. As other parts of the world get hotter, we will start to see more of these one-in-a-million-year events. There is one big difference though. Many of the previous changes in our planet's history were caused by volcanic eruptions and the changing heat from the sun. These can't explain the big warming trend seen over the past few decades. If these factors had remained dominant today's temperatures should have been going down. Now we are the cause. As such we have a choice; we can change the future. We don't have to go down the road before us. We can still turn back from the gathering storm. The longer we leave cutting emissions, the worse the problem will become. Otherwise, if ever any descendants of ours left thousands of years hence to pick through the ice, mud and blood of today, they'll wonder why we ignored the warnings. We've got to change our ways.

Adam Rutherford: That was Chris Turney from the University of Exeter. His latest book, 'Ice, Mud and Blood: Lessons from Climates Past' is out now published by MacMillan Science.

Jingle

Kerri Smith: We heard earlier about the characteristics and evolution of the wonderfully strange platypus, but our own family tree also comes in for examination in Nature this week. A team led by Rolando González-José of Argentinean Research Council, CONICET has come up with a new way of sussing out the evolutionary relationships between animals and applied this method to humans. They take into account the fact that many characteristics are not discrete like being either tall or short, but vary along a continuous line. Many current methods break these continuous traits up, a process that the team called discretization. When the team looked at four different human characteristics, they were able to shed new lights on many theories of human ancestry, including the idea that Neanderthals are indeed are a separate species from Homo sapiens. Here's Rolando González-José. Nature advance online publication (4 May 2008)

Rolando González-José: This is just an initial attempt to join very, very separated disciplines like quantitative genetics and evolutionary development studies, which are focused on the nature and the evolution of character itself and the cladistic practices which is focused on the use of characters to reconstruct phylogenetic relationships.

Kerri Smith: Currently, how do we analyze species characteristics and species relationships?

Rolando González-José: The traditional view is centred on a discretization of continuous traits. Continuous traits are divided in two character states, for instance broad cranial vaults versus narrow cranial vaults and we add that the entire spectrum of shape variation should be considered as a fact and discretizations are reduction of the real pattern of variation of many, many complex phenotypes.

Kerri Smith: So tell us how you have gone about improving on these methods then? What have you factored into your new cladistic method?

Rolando González-José: This is a controversial issue because you have a lot of alternatives in order to consider the continuous nature of many complex phenotypes. We proposed to use the advantages of geometric morphometrics which is the most powerful approach to shape variation and before you compute a cladogram or a tree representing relationships among organisms you have to work on the relationships among the traits that you are submitting to the cladistic analysis. You have to put into the framework of your cladistic analysis, hypothesis about modularity about how the traits in your database relate each other. We have used just four characters which represent the retraction of the face, the globularity of the vault of the skull, the flexure of the cranial base, and the morphology of the masticatory apparatus, just as an initial hypothesis about the skull modularity and we have submitted it to cladistic analysis which treats continuous traits as such.

Kerri Smith: And when you did this then for the Homo species what were your results? How did they differ to current methods and how are they similar?

Rolando González-José: The results show a very interesting phylogeny, which is in many ways concordant with previous phylogenetic reconstructions, but which present some interesting differences with previous approaches. Some previously reported monophyletic groups, for instance the robust australopithecines are not longer considered monophyletic. They behave as a paraphyletic group, not sharing a common ancestor. Another interesting difference is with some of the previous phylogenetic reconstructions concern Neanderthals and Homo sapiens, our species. In our analysis, Neanderthals do not form a monophyletic clade with Homo sapiens but with Homo heidelbergensis, the species which many scholars believe are the most recent common ancestor joining Neanderthals and our species. So in our analysis, Neanderthals and heidelbergensis form a monophyletic clade or a monophyletic group, which is separate from our species and this goes to counter some views stating that Homo sapiens and Neanderthals are the same species.

Adam Rutherford: Finally this week, an ingenious method of gauging the age of cells reveals why it is so hard for dieters to keep fat off. Here's Charlotte Stoddart, 98% fat free.

Charlotte Stoddart: Obesity is increasing not only in the western world but also now in many developing countries, posing a serious public health problem by enhancing the risk of, for example, heart disease and type 2 diabetes. From diet plans to exercise regimes, we are bombarded by advise on slimming, but in reality it can be tough to lose weight and then keep it off. Now researchers from the Karolinska Institute in Sweden think they know why. They found that the number of fat cells, or adipocytes, in the body stays constant throughout adulthood, each cell shrinking or growing, as we lose or gain weight. They also investigated fat cell turnover by looking at markers imprinted on cellular DNA as a result of nuclear bomb testing during the Cold War. To find out more, I spoke to lead author Kirsty Spalding and to her colleague Peter Arner, who works at the Karolinska University Hospital. Kirsty first. Nature advance online publication (4 May 2008)

Kirsty L. Spalding: So we looked very much at the number of fat cells in adults and then we combined this with research that already existed in the literature with the number of fat cells seen in childhood and adolescence, and what we found is that unlike in childhood where the fat cell number is increasing that the fat cell number plateaus off and becomes very stable during adulthood across all body masses so from lean through to obese.

Charlotte Stoddart: Does this mean then that even if we put on weight during adulthood the number of fat cells in our body doesn't change?

Kirsty L. Spalding: We looked in our study at the opposite of that which was, we looked at people that lose a lot of weight during adulthood and if the people that were going in for gastric banding surgery and we took a biopsy of their fat and then two years later when they lost a lot of fat, we looked at what the story was with their fat cells and we found that whilst the volume of the fat cells decreased there was absolutely no change in number.

Charlotte Stoddart: If then, when we lose weight, the number of fat cells in our body doesn't decrease? What sort of implications does that have for people who lose weight and want to keep that weight off?

Kirsty L. Spalding: Well, I think this data indicates that it could be quite difficult for people to keep their weight off since there is no possibility as our data shows, for them to actually you know reduce the number of fat cells.

Charlotte Stoddart: Tell me a bit more about this study that you did to look at fat cell turnover because that's a pretty tricky thing to investigate, but you found a really neat way of doing that.

Kirsty L. Spalding: So during the period of the cold war, the mid 50s to the early 60s, there was a lot of above ground nuclear bomb testing and in essence what that did was, cause an increase in the amounts of radioactive carbon i.e. carbon-14 in the atmosphere and this has then been incorporated into the DNA of cells. So we can actually take a population of cells, we can take out the DNA and by determining the level of carbon-14 in the DNA we can then figure out what year these cells were born.

Charlotte Stoddart: So what did you conclude then about fat cell turnover?

Kirsty L. Spalding: Basically we are all making fat cells as adults unfortunately and it is quite a high amount of turnover going on. We are having about 10% new fat cells made every year, but this is balanced as well by a 10% loss in order to keep the number tightly regulated in adulthood.

Charlotte Stoddart: Old fat cells are dying but we are also making new fat cells to replace those and the overall number of cells is staying roughly the same in adulthood.

Kirsty L. Spalding: Yes, exactly that's what we found.

Charlotte Stoddart: Thank you very much Kirsty. Turning to you then Peter, if the number of fat cells that we have is largely determined in childhood and adolescence, does this mean that childhood obesity is a particular problem that if we gain a large number of fat cells when we are young, then it is going to be particularly hard to stay slim in adulthood?

Peter Arner: Yes, because if you settle the generation of fat cells when you are young, it will be then very difficult of course to change that number once you are grown up. It's very good for the child not to be overweight during growing-up period, because that is the period when we really trigger the hormone effects that we are going to generate in the future. So slim and healthy, that's the thing.

Charlotte Stoddart: How about when we are adults then? Will your findings about fat cell turnover help us to develop new therapies to combat adult obesity?

Peter Arner: We think so, we think if it will be possible for an obese person to make a trick so that person doesn't generate many new fat cells over time, then it probably is more easy for such a person to lose weight and if he has lost weight to keep that low weight, because he don't then have so many new fat cells coming up which need to be rapidly filled up. That we hope we will be able to get in the future. This is not just, a good news so to say for the obese persons, it's may be a better news for these people, who involuntarily lose a lot of adipose tissue or who cannot make adipose tissue, because these are severe and life threatening conditions. If we, in this group of patients, could increase their formation of new fat cells, we might be able to help them to build up fat stores and be able to cope better with their energy demands and for me that is may be even more important than to treat obesity, because we can treat obesity with various types of lifestyle interventions, but with these people who involuntarily lose weight, we are really helpless.

Adam Rutherford: Peter Arner there and before him, Kirsty Spalding of the Karolinska Institute in Stockholm, Sweden. Now, that's all for this week's show and we are in a celebratory mood: http://www.nature.com has won a Webby.

Kerri Smith: That's right in the Internet equivalent of an Oscar our website won the judges vote in the science category, beating off stiff competition from NASA and the American Museum of Natural History.

Adam Rutherford: Now you will be relieved to hear that unlike the Oscars, we won't be thanking God and our collective mothers, Webby tradition dictates that the winners give a 5-word acceptance speech. So you can e-mail us with your suggestions.

Kerri Smith: That address is mailto:podcast@nature.com and may I suggest "All Hail the Nature Podcast!!!" I'm Kerri Smith.

Adam Rutherford: And I'm Adam Rutherford, thanks for listening.

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