Nature Podcast

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Kerri Smith: Coming up, survivors of the 1918 flu pandemic.

James Crowe: These folks are becoming more rare each year, so there is a little window in time that we can study those who were first exposed in 1918.

Kerri Smith: We discover that 90 years on, their immune systems are still primed to fight the virus.

Geoff Brumfiel: And SciFoo camp, Nature's annual 'unconference'.

David Bauer-: It's sort of this uninhibited weekend where people are doing science and having fun, as science is a drug if you will.

Geoff Brumfiel: This is the Nature Podcast. I'm Geoff Brumfiel.

Kerri Smith: And I'm Kerri Smith.

Kerri Smith: First this week, you might think all fat cells are bad news, but James Morgan has tidings of some good guys among them.

James Morgan: If I told you the solution for tackling obesity was to grow more of fat cells, you may think I was feeding you a load of baloney, but in fact there is one type of fat, brown fat cells, whose role is to burn off calories and generate body heat. This week two groups from Harvard Medical School announced that they've identified the molecular switches which trigger brown fat cell development. Proteins, which they believe could be candidates for drugs to tackle obesity. To find out more, I spoke to Bruce Spiegelman of the Dana-Farber Cancer Institute. Nature 454, 961–967 (21 August 2008)

Bruce M. Spiegelman: Well, what we know is that brown fat is a cell type devoted exclusively to energy expenditure, which means wasting chemical energy, taking energy in the body, fat, and ATP and converting it to heat. It does this as a defence against the cold and as a defence against obesity.

James Morgan: Sure, so if we can learn how brown fat cells form, then presumably we could encourage that as a treatment for obesity.

Bruce M. Spiegelman: What a great idea. Now that's exactly the sort of mindset that has driven our pursuit of these goals for a quite few years.

James Morgan: So, did you go then looking for the switch that turns on the development?

Bruce M. Spiegelman: Yes. Exactly and so in a paper in 2007, we identified PRDM16 as a regulator of brown fat and in the new paper by pushing it up and pushing it down, we learned something kind of shocking which is that brown fat is actually a derivative of muscle. We and everybody else assumed that since there were two kinds of fat cells, white fat cells and brown fat cells that there were some common fat cell precursor that, kind of, split into white fat or brown fat and what we showed by manipulating this PRDM16 molecule is that brown fat cells are a one-gene switch from skeletal muscle and put in other ways skeletal muscle is a one-gene switch from brown fat.

James Morgan: So you have now identified a protein, which switches this precursor on to the brown fat cell development pathway.

Bruce M. Spiegelman: Yeah.

James Morgan: Could this conceivably be a drug therapy for obesity?

Bruce M. Spiegelman: Exactly, I would say there would really be two ways of thinking about this. One is to identify chemical matter either the natural molecules that do this or synthetic chemicals that are capable of doing this or possibly transplantation where we could take an individual's own white fat cell precursors or muscle cell precursors, expand them in a dish, put PRDM16 into those cells and then put them back into the patient's own body. That's called autologous transplantation and that is not far fetched because that is actually done with fat right now for cosmetic surgery. You know, liposuction fat is taken out and in certain cosmetic surgeries fat cells are put back.

James Morgan: So, do you think that stimulating the development of brown fat cells would be a better treatment than the treatments that we have at the moment?

Bruce M. Spiegelman: Yeah, the treatments we have are very ineffective. The fact is we don't have many effective treatments for obesity. As far as I know, the only substantially effective treatment for obesity is Bariatric surgery, bypass surgery and that is effective, but you know that is a rather extreme treatment, only used for people who are, you know, really have morbid obesity and you know, certainly I think everybody would agree that medical treatments of other sort would be very, very useful.

James Morgan: And could there be any trade offs in encouraging the growth of brown fat. I mean are we suddenly going to get really hot because these cells produce lots of heat.

Bruce M. Spiegelman: You know I am glad you asked that. Not really, I mean because it's really a matter of degree your body can deal with increased energy expenditure, increased heat production at a moderate level very easily by, you know, expanding peripheral blood flow etc, etc., so this is a very important point. We really are not talking about, you know, increasing energy expenditure 30%, we're talking about people who are obese are only a couple of percent out of balance. So presumably the therapy would only change it by a couple of percent and that would most likely be imperceptible.

James Morgan: While Bruce was studying the switch which turns muscle precursors into brown fat cells, his colleagues at Harvard's Joslin Diabetes Centre were focusing on another protein, which governs the switch, BMP7. I asked Dr. Yu-Hua Tseng what the two groups find to do to turn the research into a treatment. Nature 454, 1000–1004 (21 August 2008)

Yu-Hua Tseng: One can potentially take either the native protein or besides small molecules that mimicking BMPs effect and use it to treat individuals with obesity. Specifically for people who are genetically predisposed to obesity and they cannot lose weight by conventional diet and exercise.

James Morgan: So, could we possibly see yourself and Dr. Spiegelman collaborating in future to develop treatments for obesity?

Yu-Hua Tseng: Oh, definitely, definitely, we would love to.

Kerri Smith: Yu-Hua Tseng, there talking to James Morgan. Coming up in just a moment, suicidal Salmonella, but first gold could be making chemistry greener, Geoff.

Geoff Brumfiel: That's right. It's a little surprising because gold normally isn't very reactive that's why it's shiny, it doesn't oxidize, but it turns out that magic clusters of just 55 gold atoms can actually speed up certain reactions. Owain Vaughan did the work at Cambridge University, but has since joined the staff of Nature Nanotechnology. I sat down with him to discuss how these tiny clusters could replace more environmentally damaging catalysts. Nature 454, 981-983 (21 August 2008)

Owain P. H. Vaughan: For a long time, it was thought that gold was a pretty useless metal as a catalyst, but I think around 20 years ago, it was shown that if you make it very small, it becomes highly active for a range of oxidation reactions.

Geoff Brumfiel: And how small are we talking?

Owain P. H. Vaughan: Yes, I think the initial discoveries were around five nanometres.

Geoff Brumfiel: Really, okay and then what can we use it for when you get that small?

Owain P. H. Vaughan: Yes. One of the first reactions that they looked at was CO oxidation, which is in fact the reaction in your catalytic converter does in the car.

Geoff Brumfiel: Now, it might be surprising to people that the size of a particle would change its chemical properties, but I gather this is actually fairly common in nanotechnology.

Owain P. H. Vaughan: Yeah, exactly. As you make things smaller, their properties just change.

Geoff Brumfiel: And why is that?

Owain P. H. Vaughan: I think there is lot of different reasons. In terms of gold, I think there's been a lot of debate about the reasons why and one of them is to do with support it's on, so it's the gold that's usually on titanium, which can modify the electronic properties of the gold.

Geoff Brumfiel: When you said the gold is on titanium, what do you mean?

Owain P. H. Vaughan: In a lot of cases with catalyst, they are supportive to the material, and this is to disperse the metal, so to stabilize it, and spread it out. That's one avenue and that's been important in the past, but I think in our case, we used inert supports so we could rule this out, so the properties we see and the results we get are due solely to the gold itself.

Geoff Brumfiel: So, let's talk a little about what you did here?

Owain P. H. Vaughan: So previously they looked at particle sizes around five nanometres. So we looked at even smaller particles, so our gold 55 particles are actually around one and a half nanometres and we found that when go that small, it can have another range of reactions that it does.

Geoff Brumfiel: How did you make it that small? I mean, how did you get particles that small?

Owain P. H. Vaughan: Yeah, so sometimes it's difficult to prepare a particle that's small using some standard techniques and another problem is you usually end up with a range of sizes, so you get a few at the size you want, but then it's usually a large distribution, so we used a cluster chemistry to build this. So we had 55 atom clusters with a ligand sheath around them, so these are organic molecules around to stabilize the gold 55. We then put this on a support and then removed the ligand sheath, so therefore, we could access around one and a half nanometre particles.

Geoff Brumfiel: And how did you get exactly 55 atoms, so say you dropped and counted them?

Owain P. H. Vaughan: Not quite. So, actually the gold 55 magic clusters had been previously described a while ago, I think in the early '80s they were first discovered, but I think it was the first time those clusters have been applied to catalysis.

Geoff Brumfiel: So, once you these little cluster of atoms then you had them all stabilized, what did you use them for? What were you actually catalyzing?

Owain P. H. Vaughan: Right. So previously in gold catalysis, it had been shown they could do selective oxidation reactions and these are reactions to produce things like epoxides, important chemical intermediates that are used to make a range of products, things like plastic, but with gold previously, it always required some sort of additive to kick the reaction off, unless it limit this wider applicability. So, we showed that when we make these particles of around one and a half nanometres, you don't need these additives, all you need is dioxygen. So I think the key fundamental result in this is that the gold particles can disassociate dioxygen and I guess in a wider context, it's showing that you can carry a partial oxidation reaction only using dioxygen as currently the technologies to produce these epoxides aren't environmentally friendly homogeneous roots involves things like chlorine or peroxides our gold catalyst could perhaps be used as a much more efficient and greener catalyst.

Kerri Smith: Owain Vaughan, formerly of Cambridge University and now one of the flock here at Nature Towers.Jingle

Kerri Smith: Those suicidal Salmonella are up next. Before leaving for sunnier climes this week, Adam learnt more about them.

Adam Rutherford: When we talk about game theory, most people think about two prisoners bargaining with their captors to get themselves the best deal. The prisoner's dilemma is a very useful model for animal behaviour. But cooperation and self-sacrifice are not just limited to animals and people. A new study by a team from the Institute of Integrative Biology in Zurich, Switzerland has been looking at the way bacteria can self-sacrifice for the greater good. I spoke to lead author, Martin Ackermann, and started by asking him, how different models of cooperation work. Nature 454, 987–990 (21 August 2008)

Martin Ackermann: Cooperative act can be divided into two types. In the first type of cooperative acts, every individual engages in cooperation and also benefits. In the second type of cooperative act, only few individuals engage and the other individuals that do not engage in the cooperative action benefit from the resulting public good. Example of the second type are worker individuals in social bees. Worker individuals do not themselves reproduce and obviously in a bee species, if all individuals would be worker individuals there would be no progeny produced at all and so in the second type of cooperative act, they are only possible if only a fraction of individuals expresses them.

Adam Rutherford: Okay and so we come to this concept of phenotypic noise, which helps understand the distinction between these two different models. Can you explain what phenotypic noise is?

Martin Ackermann: One way of looking at phenotypic noise is to look at two bacteria that emerge from the division of a single bacterium. Mutations happen very rarely, so usually cell division does not lead to any genetic change, so the two individuals that result from cell division are a clone. Typically they also live in exactly the same environment, so one would expect them to have exactly the same properties. However, if one closely looks and observes that this is very often not the case to express this in genes and have different biological traits and this is known as phenotypic noise.

Adam Rutherford: And in your study, you have in fact focussed on bacteria rather than bees or higher organisms. Can you tell us what you've done and what was significant about Salmonella?

Martin Ackermann: Salmonella are important pathogens of humans and understanding how Salmonella infect and how division of labour allows them to infect the host is essential for our understanding of the infection process.

Adam Rutherford: And tell us a little bit about the experimental setup because obviously you can see game theory in action in people by doing sociological studies and you can see it in bees by looking in hives, but when you've actually got bacteria on a dish, what are you looking at?

Martin Ackermann: So, for those studies it was essential to be able to see what biological properties the given bacterium expresses and to visualize we used fluorescent proteins and by choosing the right types of proteins that are activated under certain conditions, bacteria that belonged to the self-sacrificing group shine up in fluoresce green, but other bacteria that do not engage in the self-sacrifice remained dim.

Adam Rutherford: Extrapolating from your results, what does this model that you've observed, what does it tell us about other populations such as higher organisms?

Martin Ackermann: This model gives us a new perspective or sheds new light on the division of labour in populations. People have often considered that the formation of two groups that divides labour involves signalling between individuals and this communication then determines which individual performs which act. This study suggests that communication is not necessary. It suggests that each individual can just basically flip a coin and based on flipping of the coin then decides what it should do.

Adam Rutherford: But if it's a random process, if it's like a flipping your coin as you say, there must be some process that mediates the proportions that go into the different phenotypes, otherwise, you might have a complete self-destruction of a population.

Martin Ackermann: Yes, that's very important point. If this act of self-destruction would be biologically hot-wired, so if all individuals would express it, then the whole population can immediately go extinct. So self-sacrifice can only exist, if not all individuals actually do express the self-sacrificing act and we believe that the probability that the given individual will express the self-sacrificing behaviour might be genetically determined.

Geoff Brumfiel: That was Martin Ackermann talking to Adam. We'll be hearing about a science meeting with a difference shortly, but first Charlotte Stoddart seeks out some very old but still very immune influenza survivors.

Charlotte Stoddart: As we get older, our immune system usually wanes becoming less able to fight off diseases, but survivors of the 1918 flu pandemic are still, 90 years on, primed to fight the disease, as James Crowe and colleagues at Vanderbilt University in Tennessee show in this week's Nature. What's more the antibodies produced by these survivors are some of the most potent virus-busters ever discovered. The 1918 flu pandemic killed around 50 million people and as James explained to me understanding the immune response of survivors could help prevent a similar outbreak in the future. Nature advance online publication (17 August 2008)

James E. Crowe Jr.: A number of studies have shown that this is a highly pathogenic virus and yet very little information has come out so far on whether or not humans can mount an immune response to the virus and this study is really the first to show that survivors of the infection with the virus really did mount very good immune responses.

Charlotte Stoddart: Was it difficult to find subjects for your study?

James E. Crowe Jr.: One of the co-authors made it known really to the press that he was interested in collecting individuals and although individuals of this age are relatively sparse in the population, when he got the word out, he was bombarded by inquiries of individuals who were interested in donating and they appeared to be highly motivated to participate in this research and in fact because of the memory of family members being involved in the pandemic, this was another personal connection of some of these donors and spurred their interest in participating.

Charlotte Stoddart: That's great that you could get so many people involved and I guess this was really your last chance to do a study like this.

James E. Crowe Jr.: Well that's right, these folks are becoming more aware each year, so there is a little window in time that we can study those who were first exposed in 1918 and we obtained blood from these extremely elderly subjects and showed that all of them retained antibody responses to the virus.

Charlotte Stoddart: And what did you find then when you studied these antibodies in the lab.

James E. Crowe Jr.: Right, well the surprising thing was that we found any cells in the blood at all of these individuals because these types of influenza which were called the H1N1 viruses from the early 20th Century have not circulated in the human population since about the 1940s or early 1940s and therefore it wasn't expected that individuals would maintain these cells floating around in the blood for such a long time. So, first that was very surprising to find they have the B cells in the blood at all and second, the antibodies that we isolated are some of the most potent antibodies against the virus that had ever been discovered and that was very surprising because I think we all have the notion that elderly people have a laming immunity or weakened immunity.

Charlotte Stoddart: Does this suggest then that our immune system is actually much better at remembering diseases that we encountered years and years ago than we expected?

James E. Crowe Jr.: It's well known that if we immunize or study infection in elderly subjects with new antigens for instance new flu vaccines that they don't always mount a robust immune response during the elderly period to new antigens. So it may be that their memory of infections that they had at a very remote time or even as children may be better than their ability to respond to new antigens, which is quite interesting because it has parallels with cognitive memory and that elderly often can remember events from childhood whereas they can't retain short-term memory events. So it has almost a metaphor in their immune system perhaps.

Charlotte Stoddart: James what is this about these particular antibodies that you isolated that makes them so potent against the virus.

James E. Crowe Jr.: These antibodies have very interesting molecular features, when we were able to obtain the antibody genes and sequence them we found that they had two to three times the normal frequency of mutations in them. Antibodies normally gather mutations in order to help the antibody fit better to antigens, but these particular antibodies had a lot higher frequency of mutations, which in turn allow them to bind much tighter. These are some of the highest affinity or best binding antibodies that have ever been described to a virus.

Charlotte Stoddart: Like the H5N1 strain that we are worrying about today, we think that the 1918 virus came from birds. So, what can we learn from your study then about tackling future outbreaks?

James E. Crowe Jr.: There's nothing particularly unusual about the replaces in the virus that are recognized in these bird influences, compared to the regular seasonal flues. In that case, let's hope that we can develop antibodies to any of the avian influenzas. In fact, we are currently attempting to produce human monoclonal antibodies against the avian influenza strains that are potential pandemic threats right now.

Geoff Brumfiel: Vanderbilt University's James Crowe.

Kerri Smith: And from flu to foo. Science Foo camp to be more precise. Still not sure what I'm talking about. Let attendee David Bauer explain.

David Bauer: I don't know, it's something to me like what I would imagine a hippy commune would be like, except it's only for 3 days and it's in the middle of Google, but everything's free and there's free food and free science and there are tents in the lobby and sleeping bags and people sitting around talking about science and playing guitar and doing science rhyme and poetry and it's sort of this uninhibited weekend where people are doing science and having fun, as science is a drug if you will.

Kerri Smith: It might be clearer after that why its organizers call it an Unconference. Nature's Ollie Morton is just back from the meeting from in California has joined me in the pod to further elaborate. Olli what's the big idea here. What is SciFoo?

Oliver Morton: I don't think SciFoo really limits itself off to one big idea. It's lots and lots of big ideas all going at once, but as per the setting for what is unavoidably in the context often called a happening or an unhappening is that three organizations, Google, ourselves at Nature Publishing Group, and the O'Reilly Publishing Company get together and invite a large number of scientists from all levels of the profession, but all of select proven track record on being smart and clever, and interested and Google very kindly makes available a set of rooms at what they call the Googleplex, their corporate headquarters and there's a big white board at the beginning of the meeting and people write down what they want to talk about and sessions arrange themselves spontaneously on that basis, and by the end of the first evening, you've got the program for an extraordinarily wide ranging conference that you then go to for the next day and a half.

Kerri Smith: And I suppose crucially, it's not just scientists who are good at one little tiny aspect of science, but people who might have a sort of broader view of the scientific enterprise.

Oliver Morton: I think it works by having both. It has real experts, who really do care about one particular thing, but it puts them in a context, where they can learn from other people and go to other things. I think there are two interesting approaches. Some people go to things entirely outside their specialty. Some people go to things that they are kind of specialized in, but benefit from hearing what smart people outside actually want to know about that. So, I am sure it's very interesting for someone like Martin Reese, the astronomer Royal to hear what smart people who don't think about astronomy much want to ask about astronomy, you know, what are their questions.

Kerri Smith: And in fact we have a little clip of Martin Reese on what he feels of the conference coming up in just a moment, but first of all, let's hear from Brian Cox who fits into this category of people who do one particular science who went to other scientific talks.

Brian Cox: I almost exclusively avoided the physics talks and I went to talks about global energy issues, about climate change, about biology, you know, just the whole region of science that you never get to hear, if you go to a physics conference. These multidisciplinary conferences actually allow you to be a science fan again. You remember that actually what you are interested in is the way the universe works and the science is whole and it reminds you of that.

Kerri Smith: Physicist Brian Cox there. Next up, Chris Patil of the Ouroboros Block.

Chris Patil: Well, it's different in any number of ways. The two primary ways are the diversity of the things that I've heard, and the second way is that rarely I have ever said a conference will have changed the way I approach my profession and this will definitely meet that criteria.

Kerri Smith: And finally Martin Reese, cosmologist and astronomer Royal.

Martin Reese: Well I suppose it's what you call a happening or a sort of many Woodstock of the Mind as it were and what I learnt from this is exciting developments in a whole range of subjects, particularly people who one doesn't normally encounter and of course what is even more important is that most of us academics are within the academic closet most of the time and I think it's very important to get outside that closet and realize that intellectual activity is not just one's academics do, it's what many other people do.

Kerri Smith: So, as we've heard from those quotes then, it's definitely capable of changing how scientists view the work that they do, but Ollie what was your favourite aspect of the meeting, how did that change. Did you change your views?

Oliver Morton: It certainly taught me a lot of things and I was one of the people who, sort of, like drilled down at being neck deep in all the energy stuff we've been doing recently and I went to a lot of the energy and climate sessions and what struck me was that some are optimistic and some are pessimistic but they all sort of agreed on just the sheer scale of intervention that's now necessary and so you can get these real enthusiasm, wonderful talk by one of the guys at Google on the idea of building huge solar power plants. Somehow out there in the California sun it really does feel possible, but it also feels monumental, there's a sense of real scale there that's extraordinary and there was a session that started off being about mass and turned into how to basically put small asteroids into glow bags and experiment on them and I thought that was great.

Kerri Smith: Did you come away with a sense that people here are in any way idealistic? I mean, Woodstock we've heard it referred to as a hippy commune that's taking place on the sun soaked California coastline?

Oliver Morton: Oh! Yes absolutely. It's idealistic, and it's full of people who both want to enjoy themselves and want to change the world, I mean, there were lot of people there talking about developing country health issues for instance this time and that's something that the philanthropic arm of Google is getting very interested in. So yes, it's undoubtedly idealistic, but it's also full of people who know quite a lot about making money and about how the world actually works, it's just a mixture of people that I don't think you'll come across anywhere else. There's a particular form of inspiration, I think, everyone involved in my experience, I've been to a couple of now, goes away feeling that they can do more than they could when they get there and that's pretty good investment in 48 hours.

Kerri Smith: Great stuff, thanks Ollie. Special thanks also to SciFoo attendee and science comedian, Brian Malow, who recorded those clips for us. Find more info and photos of SciFoo on his website, That's all from us this week.

Geoff Brumfiel: We'll be back next week with transport of the future and how kids learn a sense of fairness. I'm Geoff Brumfiel

Kerri Smith: And I'm Kerri Smith. Thanks for listening.


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