Nature Podcast

This is a transcript of the 21st 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 (, which also contains details on how to subscribe to the Nature Podcast for FREE, and has troubleshooting top-tips. Send us your feedback to

Kerri Smith: Coming up this week, is obesity really just about how many pies you eat?

Jeffrey M. Friedman: Genes play a very prominent role, the major role in fact, in determining whether or not someone becomes obese, when sufficient calories are available.

Adam Rutherford: And could anything living on Earth have survived these hostile conditions?

Oleg Abramov: By hot, I mean 1000 degrees Celsius or more. So if you were standing on the surface of the Earth, you would have been pretty much melted, if not vaporized.

Adam Rutherford: Answers to that scorcher later in the show. Plus we bring you the choicest cuts of the week's Science News. This is the Nature Podcast. I'm Adam Rutherford.

Kerri Smith: And I'm Kerri Smith. First this week, we are examining the relationship between Down's syndrome and cancer. People with Down's syndrome are known to be less susceptible to cancer and naturally researchers would like to know why. Down's syndrome individuals have an extra copy of chromosome 21, giving them three copies of the genes that live there, rather than two. And so this seems like a good place to look for genetic factor that protects them from cancer, but it's not clear which of these hundreds of genes is protective. In Nature this week, a team led by Sandra Ryeom at the Children's Hospital in Boston, Massachusetts pinpoint one possible candidate called DSCR1 or Down's syndrome candidate region-1. Nature advance online publication (20 May 2009)

Sandra Ryeom: The reason we came upon on DSCR1 is we know that it blocks the actions of a protein called calcineurin. So then my work translated to the cancer field when I realized that this pathway was very important in endothelial cells, the cell type that make up the blood vessels that are necessary for tumours to grow and then this is when I became interested in the Down's syndrome population when I realized DSCR1 was also on chromosome 21. So you know, very intriguing to think that this gene on chromosome 21 played a role in blocking blood vessels from growing and that this may be a very critical step in protecting against cancer.

Kerri Smith: And that was indeed what you wanted to go and test in this paper.

Sandra Ryeom: Correct.

Kerri Smith: So, how did you go about that, how did you test whether this was indeed protecting individuals against cancer?

Sandra Ryeom: The first thing we did was to use a series of mouse models. So there is a Down's syndrome mouse model that we received from our collaborator, Roger Reeves and we were able to first show that mouse model of Down's syndrome show the same tumour suppression or protection against tumour growth that the human population did and then once we established that what we did is we made a mouse with just three copies of DSCR1. So instead of three copies of chromosome 21, we made what we called, you know, trisomic DSCR1, so only this gene alone to see what contribution this had in protecting the tumour growth. You know we made a mouse with three copies and then we put tumour cells in it and measured the growth and we found that it was significantly blocked and then the other thing we did is we took the Down's syndrome mouse model, which has three copies of all the genes on chromosome 21, almost all the genes on chromosome 21 and we took away one copy of DSCR1. So we put it back to the normal two copies and taking away that third copy, we found really significantly abrogated the tumour suppressive effects.

Kerri Smith: So that pretty much nailed it then.

Sandra Ryeom: Yes. It did and then the key experiment though, so that's a mouse model right and one of the issues in the mouse is that there is only 17 chromosomes, right. So chromosome 21 in the human is spread across three chromosomes in the mouse. So one of the criticisms initially was, well that's all well and good in this artificial mouse model, but mice don't get Down's syndrome. So how do we know this is true in the human population. So what we did was with our collaborator, George Daly at Children's Hospital, we were able to use human cells from Down's syndrome individuals and normal individuals. So he took basically skin cells from, you know, a Down syndrome individual and a normal individual and made them into stem cells and then we were able to take those cells with them and inject them into mice and watch them form these benign tumours and measure blood vessel growth and we found that this also mimicked the same thing we saw on the mouse that the cells from the Down syndrome individual did not form blood vessel or at a very very low level compared to the normal.

Kerri Smith: Some other groups have found different genes, also from chromosome 21 to be involved, like Roger Reeves and his team from Johns Hopkins University. Here he is telling us about his findings on the podcast in January last year.

Roger Reeves: So we initially took a mouse model of Down syndrome and when we crossed that Down syndrome mouse model to a mouse model that gets cancer, we found that the number of tumours was significantly reduced and so we next came up with a candidate that we thought might be contributing to the lower tumour frequency and that gene was the Ets2 transcription factor. We think that what Ets2 might be doing is making the cells very sensitive to program cell death that is a normal occurrence when cells begin to undergo the process of transforming from normal cells to cancer cells.

Kerri Smith: So Sandra, how does this fit in with what you found?

Sandra Ryeom: So we think it's probably two fold. One that they have a set of genes that really inhibit normal cells from becoming cancer cells, but we think more importantly that there is a set of genes that really block the blood vessels from nourishing these cells. I mean the cancer protection in the Down syndrome population seems so complete that I think it's got to be multiple mechanism.

Kerri Smith: One final question then, could you use what you know now about DSCR1 and its involvement in cancer protection in these individuals to develop therapies that could combat cancer in people without Down syndrome.

Sandra Ryeom: So that's exactly what we're doing now. So what we've done now is chopped up DSCR1 to little pieces and now we are testing various pieces to see, you know, which one has the effect of blocking these endothelial cells from growing and forming blood vessels and we are trying to target them specifically to the cell type. So you know, the amazing thing is clearly this population, the Down syndrome population only has three copies, so it only has a little bit extra of this gene. So we think, if we can just raise the level slightly, this could be protective for the rest of us.

Kerri Smith: What would that treatment look like?

Sandra Ryeom: We are trying to make it a peptide, so a little protein fragment, so we would inject it or take it orally, you know, if we can get an oral formulation, sort of like a vitamin, type of therapy, right. So we think, you know, in a perfect world, where we would love to be able to deliver this, where it has a tag and goes directly to the cells, gets inside the cells and you only have little bit extra. So if the rest of us took it, you know, occasionally, once a week so to think and keep those levels high so that those endothelial cells always stick by it.

Kerri Smith: This is a therapy you would envisage giving to everyone then as a kind of protective thing?

Sandra Ryeom: Yes. I mean that would be, you know, because we keep thinking that you know, this population has this gene expressed in slightly elevated levels and there is no real effect to it outside of protective, right. So it doesn't seem to be toxic or cause any other issues. You know, we don't think it's associated with any of the other respiratory or cardiac issues. We don't think it's associated with any of the neurologic learning or memory issues, so you know, our thought is, it's probably nontoxic and probably you know, could be tolerated by all of us.

Kerri Smith: Sandra Ryeom there.


Adam Rutherford: Coming up, a terrible swine flu song and how your genes might be stopping you from losing that stubborn spare tire. But first, certain parts of the Earth might seem pretty hostile to life; snow covered poles or acidic lakes and seas. But as Geoff Brumfiel found out, they are nothing compared to the conditions of 3.9 billion years ago.

Geoff Brumfiel: 3.9 billion years ago was not a happy time here on Earth. The planet was under constant bombardment from asteroids and other space debris. The repeated impacts were powerful enough to extinguish any life on the surface. But what about beneath the surface? Oleg Abramov and Stephen Mojzsis of the University of Colorado had been building models that simulate those early violent days which are known as the Late Heavy Bombardment. I called up Abramov to learn more about the odds that any subterranean dwellers could have made it out alive. Nature 459, 419–422 (21 May 2009)

Oleg Abramov: It was still an open question in the planetary science community, whether a life could have survived this kind of cataclysmic bombardment. We put together several models to investigate whether if there was any life around at the time, this is 3.9 billion years ago, could it how far live through the bombardment or not.

Geoff Brumfiel: Just give me a sense, what would you have been up against, if you are on the surface of the Earth 3.9 billion years ago in the late heavy bombardment. I mean, what was life dealing with, I mean with that heat around?

Oleg Abramov: Well, if you are on the surface of the Earth that would have been a very bad place to be. Actually from several previous studies, we know that the surface of the Earth was repeatedly sterilized by these very large impact events and we are talking impacters that were hundreds of kilometres in diameter forming craters that were thousands of kilometres in diameter and basically those huge basin-forming events would have deposited layers of very hot ejecta all over the Earth, by hot I mean, a 1000 degrees Celsius or more. So if you were standing on the surface of the Earth, you would have been pretty much melted, if not vaporized. So, we then even looked at the surface very closely because we knew that there are several mechanisms which would have sterilized the surface repeatedly. We investigated the subsurface particularly what's called the geophysical habitable zone in the first 4 kilometres or so underneath the surface.

Geoff Brumfiel: So there is stuff living in what you call the geological habitable zone today, right. I mean, there is stuff down there.

Oleg Abramov: Oh absolutely! There have been studies that involved the drilling down to 4-5 kilometres and there are viable microbes living down to those depths absolutely.

Geoff Brumfiel: How did you do this study? How did you make these calculations?

Oleg Abramov: Sure. Well, we basically replicated the late heavy bombardment on the computer and to do that we constructed several models, the first of which is what we call a stochastic cratering model and what it does is that it randomly smacks the model surface of the Earth with impacts within a specified mass and time constrains. We put all of this together into a three-dimensional model of the Earth's lithosphere and then we monitored temperatures on the surface and the subsurface and by monitoring those temperatures that allows us to calculate habitable volumes for life as well as estimate how much of the crust was melted or thermally metamorphosed by the bombardment.

Geoff Brumfiel: So you found incredibly that stuff could survive.

Oleg Abramov: Yeah, we actually found that down to depths below a few hundred meters, life could have survived the late heavy bombardment. That is because of several factors, the primary of which is that the thermal pulse of the hot ejecta that would have been deposited globally would not have penetrated very far into the subsurface, especially if there is water present. The other factor being that although at least the core of the crust would have been melted and heated fairly significantly during late heavy bombardment, it would not have happened simultaneously. The late heavy bombardment was 20 to 200 million years in duration. So you have one large impact and there is some time that allows it to cool and the near-subsurface would have been repopulated in 20 to 200 thousands years or so.

Geoff Brumfiel: Right. So how does this change the search for the origins of life, knowing that things could have survived? Does this mean that we should be looking underground for all those creatures?

Oleg Abramov: Well, I think the most important result is that it pushes back the possible beginning of life on Earth to well before the late heavy bombardment. Basically, it opens up the possibility that life started far back as about 4.4 billion years ago, around the time when the first oceans on Earth likely appeared and in terms of where to look for earliest life, perhaps late heavy bombardment just pruned the tree of life. The organisms that were on the surface would have been eliminated by late heavy bombardment but organisms that could adapt to a subsurface especially hydrothermal conditions likely would have survived the late heavy bombardment just fine. And that is interesting because some genetic studies indicate that the universal common ancestor, the ancestor of old life on Earth was what we call a thermophile, an organism that thrives at high temperatures.

Adam Rutherford: Oleg Abramov talking to Geoff.

Kerri Smith: The news chat is coming up in just a minute and blogging supremo Dan Cressey is waiting in the wings. But before that, Charlotte Stoddart chats to geneticist Jeff Friedman about why some people's diets are just not having the desired effect.

Charlotte Stoddart: Hold your breath for a few seconds and your body eventually forces you to breathe. Similarly, a wilful desire to lose weight is counted by a basic biological drive to return to your natural weight. So says, Jeff Friedman of the Rockefeller University in New York, who's written a Q&A on obesity for this week's magazine. I called Jeff and he explained to me why he thinks obesity is mostly in our genes. Nature 459, 340–342 (21 May 2009)

Jeffrey M. Friedman: Environment is clearly important because if food is not available then no one would become fat such as in a circumstance of starvation. However, genes play a very prominent role, the major role in fact in determining whether or not someone becomes obese, when sufficient calories are available.

Charlotte Stoddart: How much of a role do you think genes play because it seems like lifestyle is important. We all kind of know that, although it's difficult to lose weight, it is possibly by eating carefully and regularly exercising.

Jeffrey M. Friedman: The issue is that there is a very powerful biological system that controls weight in all of us and that sets weight to be at different levels in different individuals and the weight that each individual is set at as it were is the result of genetic and environmental factors. Now there are many personal attributes that can be controlled temporarily at least by conscious measures. So when an individual loses weight by dieting, they might be consciously motivated in the short term, but that wish to lose weight is opposed as it were by the actions of a powerful biological system that acts to maintain weight within a relatively narrow range.

Charlotte Stoddart: So are you saying then in the short term we can kind of do our best to lose weight by dieting and things but eventually the biology takes over and we can't help but eat that extra cake if that's what our genes are telling us to do?

Jeffrey M. Friedman: Yeah. I would think of it more as it's what your physiology is telling you to do and the point is that even if you lost the weight, then the power of that biological force is evident. People feel hungry all the time and the issue in essence is why do people feel hungry after they have lost weight and a secondary question might be why is that for most people the drive to eat more and regain the weight trumps the conscious desire to remain thin, while on a small number of people, the conscious drive to lose weight wins out.

Charlotte Stoddart: Indeed. So what are the answers, what does research into the biology of obesity say?

Jeffrey M. Friedman: Well, in the last 15 years, it has become evident that body weight is controlled by a powerful physiologic system composed of hormones and neural circuits whose job it is to maintain weight within a relatively narrow range. The way the system works is this, your fat makes a hormone called leptin in proportion to its mass, meaning more fat makes more leptin, less fat makes less leptin. Leptin travels in the blood and acts on neural circuits in the brain that control food intake, such that when you lose weight, leptin levels fall and this is a stimulus to eat more. When you gain weight, leptin levels rise and this is a stimulus to eat less and by such a mechanism, you can set up a biological force that resist weight change in either direction.

Charlotte Stoddart: Can this leptin pathway explain individual variation, why some people find it easy to stay slim and others pile on the pounds?

Jeffrey M. Friedman: It appears to be the case that obese people in general have a lower sensitivity to leptin. So the leptin they make doesn't work is well or elicit as powerful a response as the leptin made by a lean person. Conversely, very lean people tend to have low starting levels of leptin and appear to be particularly sensitive to the hormone.

Charlotte Stoddart: Have researchers identified any individual genes, perhaps involved in this leptin pathway or in other pathways associated with obesity?

Jeffrey M. Friedman: Yes, the defects in the genes that comprise this pathway have been shown in many cases to cause human obesity. In fact, we now know that perhaps as much as 10% of morbid human obesity is the result of a single gene defect in one of the genes within this pathway and these can include not only this hormone, leptin, but the receptor for leptin which is a molecule that reads out its signal. I should say that this is a level of single gene inheritance for a complex trait that is very high, in fact so far as I know, higher than that for any other complex trait. It's also consistent with what's known about the genetics of obesity, where twin studies tell us that somewhere between 70 and 90% of the variance in body weight can be attributed to genetic factors.

Charlotte Stoddart: So what does all this mean then? Should we hold up our hands and say there is really nothing we can do if we fought with fat and there's no point trying to lose weight?

Jeffrey M. Friedman: The message really isn't don't worry about it. The message really is focus on your health. So what's important to realize though is that one doesn't have to normalize one's weight to see a prominent health benefit and the potency of the biological system that resists weight change doesn't get engaged until substantial amounts of weight are lost. I think the problem we run into is that in the general population there is such a social pressure to be lean of average weight that people I think, set out for an unachievable goal and then lose interest because their focus is on the wrong thing. I would like to think it's the opposite than being a message of despair. I think the message is there are things you can do when you should do them, but don't expect the impossible.

Kerri Smith: That was Jeff Friedman. There's more on nature, nurture and nosh in his Q&A which is free for a week at

Adam Rutherford: Finally, Dan Cressey has been irrigating the waving fields of news and setting to work with his combined harvester. Dan, how is the yield?

Daniel Cressey: Thanks for that spectacular intro Adam. The news yield has been good this week.

Adam Rutherford: So what's up?

Daniel Cressey: Well, Austrian physicists were desperately disappointed last week when their science minister announced they were going to pull out of CERN, the big European particle research lab, but that appears to have been backtracked now. So they're probably feeling a bit happier today.

Adam Rutherford: So that's a pretty quick flip-flop, what was the original reason?

Daniel Cressey: Well, the original reason given was budget concerns as Austria pays about 20 million Euros into CERN.

Adam Rutherford: And where have they suddenly found this 20 million to rejoin the project?

Daniel Cressey: That's not entirely clear. All we know at the moment is that the Chancellor of Austria, Werner Faymann appeared to overrule Hahn and simply said Austria is staying part of CERN for now.

Adam Rutherford: In terms of the science, how significant are the Austrians in this endeavour?

Daniel Cressey: Well, it was obviously hugely important for the Austrian physicists themselves, who were expecting to work on CERN, but it was also an important symbolic thing. Only two other nations have ever withdrawn from CERN in its almost half century history.

Adam Rutherford: And who are they?

Daniel Cressey: That would be Yugoslavia and Spain, although Spain did rejoin in the 80s.

Adam Rutherford: Okay and the next story is back up in space, we talked about a new mission to repair Hubble last week. Now they are up there, what's happening?

Daniel Cressey: That's right. The final space walk to repair and upgrade the Hubble space telescope has wrapped up this week. The shuttles will be heading back to Earth for the 22nd of May.

Adam Rutherford: And it all went well?

Daniel Cressey: Yeah, there were a few teething problems, one of the bolts was stripped and they had to use a bit of brute force on that but otherwise it seemed to go well. They spent nearly 37 hours out there swapping out various components and installing new ones and then now hoping that the Hubble should work all the way through till 2014.

Adam Rutherford: All right, back to Earth for our final story. It's swine flu again but we've seen that the column inches have really gone down in the last week or so.

Daniel Cressey: That's right Adam, the column inches have come down but the WHO is clearly a little concerned on this and complacency might be setting in. Margaret Chan, its director general warned this week that the virus may have given us a grace period, she said, but we don't know how long this is going to last and no one can say whether this is just a calm before the storm.

Adam Rutherford: So, still a major threat despite the media losing interest.

Daniel Cressey: That's right, it's currently up to nearly 9000 cases of H1N1 including over 70 deaths in 40 countries around the world.

Adam Rutherford: So it's still pretty serious stuff. On a slightly more frivolous note as the column inches have gone down we have noticed that the hip-hop output for swine flu has gone up.

Daniel Cressey: That's right Adam and not just hip-hop but a whole variety of musical genres of hits have embraced the opportunities offered by swine flu.

Adam Rutherford: And we have got a selection of some of the best or possibly the worst swine flu songs coming up now.Swine Flu songs play

Daniel Cressey: I think we should make clear at this point that Nature does not endorse decapitation as a cure for swine flu.

Adam Rutherford: Absolutely no, the first one was Mike Skinner of The Streets quite a well established UK hip-hop artist and the second one a somewhat more amateur but I quite liked it. 'I don't wanna die dude'.

Daniel Cressey: Neither do I. I certainly think now the Skinner track has very high production values but it is rather lacking in lyrical content and I don't think it's going to become part of the established swine flu musical cannon really.

Adam Rutherford: But yet the second one actually was embracing the UK government's message which is catch it, kill it, bin it, referring to sneezing. So it does have a serious epidemiological message behind it.

Daniel Cressey: True and I think it also shows that the British music scene when it does things on its own back and almost DIY if you like really can provide something that is completely unique.

Adam Rutherford: Well, of course we can continue talking about the musical merits of swine flu for the rest of the show but I think it is probably best to cap it right there. Thanks very much Dan, the news blog and all of those stories and links to those dreadful songs is at

Kerri Smith: That's all we got time for this week. Thanks for tuning in and drop by again next time when we will be finding out how to experiment with the quantum world and mooning over some unusual marmosets. I'm Kerri Smith.

Adam Rutherford: And I'm Adam Rutherford. I ate all the pies.