Nature Podcast

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Kerri Smith: Coming up this week, we tear up the immunology textbooks.

Thomas Graf: This now unequivocally asks for revision of this original, simple, classical scheme of differentiation.

Adam Rutherford: We discover how rain forests keep the air so clean.

Jos Lelieveld: One can see the tropics sort of as the washroom of the atmosphere.

Kerri Smith: And we find light pushing its way through holes that should be too small for it.

Geoff Brumfiel: So, it is, sort of, like those string telephones, where you get the can and you transmit the sound wave through the string or something.

Philip Ball: It is a little bit like that, yeah except that in theory they should be sort of too small to get along the string.

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

Adam Rutherford: And I'm Adam Rutherford

Adam Rutherford: First this week, two papers in Nature look set to force a re-write of many immunology standard texts. Currently the map of how the highly specialized cells of the immune system develop is relatively straightforward. In the bone marrow, sit haematopoietic stem cells which have the potential to turn into two general type of cells -- myeloid, which includes red blood cells and platelets and lymphoid, which includes B and T cells of the immune systems. The new papers turn this on its head and show that early developing T cells lose the ability to become lymphoid cells and retain the ability to become myeloid cells. Thomas Graf from the Centre for Genomic Regulation in Barcelona in Spain has written a news and views article, which covers both papers. I spoke to him earlier today. Nature 452, 702–703 (10 April 2008)

Thomas Graf: All blood cells and including the immune cells are derived from a specialized precursor of the haematopoietic stem cell, but exactly how they branch, coming from this single precursor into the different types of blood cells has been controversial over decades and about a little bit less than a decade ago, some very important experiments were done in a laboratory in Stanford, basically stating that blood cells could be divided into cells of the immune system on the one hand and cells that are also part of the blood cell system, but which are actually the erythrocytes and the platelets, which have completely different functions in the body, and that there is an early branching of these two major compartments. Now this simplifies things a lot. This is still the major scheme, which is in many of the textbooks, but unfortunately it's not in its simple form, it's not true.

Adam Rutherford: So the textbooks say that there are two lineages -- the myeloid and the lymphoid and the B and T cells come from one, the lymphoid line and the rest including red blood cells, they come from the myeloid line. Now these two new papers, one by Bell and Bhandoola and one by Wada et al., they are saying something very different from that.

Thomas Graf: Right! So what they described now is that a particular type of immune cells, the T-lymphocytes develop in a particular microenvironment, which is the thymus, they actually originate also from a very early progenitor that is still capable of producing a large variety of different types of blood cells including B-lymphocytes and macrophages and other myeloid cells and the original idea was that actually this split there is also between lymphoid cells and myeloid cells early on, but now it turns out that actually as these T-cells develop in the thymus, they first lose the capacity to form other lymphoid cells namely B-cells, the cells that make antibodies, but retain the capacity to make macrophages and other types of myeloid cells and this is sort of a completely unexpected and different branch from what has been thought before, this now unequivocally asks for a revision of this original, simple classical scheme of differentiation.

Adam Rutherford: And how have they actually gone about demonstrating that these lines are different from what was thought? What's that in simplistic terms, how was the methodology worked?

Thomas Graf: So, what people had been shown over the last years that actually in the thymus there is a small population of cells that has the capacity to form T-cells and other types of myeloid cells, but it lost B-cell potential and that was a very strong indication that the classical scheme was not correct; however, what they could not actually pin down is the existence of a bi-potent progenitor which is only T-cell and myeloid potential and this can be only done by single cell culture analysis. So people in the new papers have painstakingly analyzed the progeny of single cells derived from these early populations and the conditions that allow the development of these different types of blood cells and then they have unambiguously shown the presence of this progenitor which had been postulated by the earlier work, but not rigorously demonstrated, so that's the new part of these papers and I think it calls clearly for revision of the existing schemes.

Adam Rutherford: So they've traced individual cells in culture and watched how they develop into different material cell types.

Thomas Graf: Yeah and they show that many of these cells have the unique capacity to form both T-cells and myeloid cells, but are not capable of forming B-cells, so this is what is the main difference to the classical scheme.

Adam Rutherford: So how do you think the field of immunology is going to react to such a profound change in our understanding of immune cell origins?

Thomas Graf: Good question and in fact I can tell you this has been controversial for a while, and people who have been advocating this change, this revision, are giving me the feedback saying "well we have said this for a long time, you know, this is really not so new for us, this is over due", while people who have been defending the old scheme are, of course, not so happy about this revision and are still trying to come up with alternative explanations that may rescue the old scheme, and so I think it actually in my opinion, it took these papers to really, perhaps put an important last point, which had to be made to make this a definite provision.

Adam Rutherford: But you think that these two new studies are a definitive full stop.

Thomas Graf: The way I can judge it from the two papers that have been sent to Nature, I would say, "yes," but you know science is full of surprises.

Adam Rutherford: That was Thomas Graf. His news and views article and the two reports are available from

Kerri Smith: Next up, any process with the word extraordinary in a title is going to be worth knowing about. To that end, earlier today Geoff Brumfiel sat down with Nature writer and all-round physics guru, Phil Ball, to find out how light can squeeze through tiny spaces. Nature 452, 728–731 (10 April 2008)

Geoff Brumfiel: Hi Phil!

Philip Ball: Hi Geoff!

Geoff Brumfiel: So, I'm here to talk to you about something called extraordinary optical transmission. Tell me a little about it.

Philip Ball: Well it's really about light getting through holes that should be too small for light to get through. It's an effect that was discovered in 1998 by some people working at the research labs at the MEC Corporation -- Microelectronics Corporation, based in Princeton and they discovered that they could get light to go through a sheet of metal that had been perforated with tiny little holes. The curious thing was that these holes were actually smaller than the wavelength of light. Now normally that's a barrier to letting the light get through. It's a little bit like trying to get an ocean wave inside the mouth of a bottle, in just one go, its just too big. So, you know, as far as the wave is concerned, the bottle might as well not be there normally, but what these people found was doing that equivalent thing with light and these tiny holes in a metal film, they found that the light did go through and come out of the other side.

Geoff Brumfiel: Do you know about how much light gets through, I mean, is it just like it comes shining through?

Philip Ball: Well, it's a usable amount. It's a significant proportion of the light that's shining on there, so you know, you could think about making sort of technological uses of the light that gets through, but the really curious thing is that it gets through at all, it just shouldn't do that?

Geoff Brumfiel: What did they I mean, I guess I understand that they've, sort of, had an idea of what might be causing the light to get through? Tell me a little about that, how does light get through these tiny holes?

Philip Ball: It was thought pretty much from the outset that what's happening is that there is some sort of interaction between the light and the electrons on the surface of the metal, so these electrons on the surface can move about; they are more or less confined to the surface but they can move about. So, you can set up waves in them and the light does that, it sort of interacts with the electrons and its starts them oscillating, creates waves in them and the key thing is that although the frequency of these oscillations is the same for the light and for the electrons, the wavelength for the electrons is smaller and that's a crucial thing because it's the wavelength that sets the limit for how small a hole they can get through. Generally speaking, they can't go through anything smaller than their wavelength. So because these surface electrons have these very short wavelengths, they can pop through the holes, whereas the light can't. Then on the other side, they sort of act as a kind of transmitter, that is still, sort of, vibrating and that re-excites the light and they re-radiate the light on the other side.

Geoff Brumfiel: I see, so, it is sort of like those string telephones where you get the can and you transmit the sound wave through the string or something.

Philip Ball: It is a little bit like that, yeah except that, you know, these are waves that wouldn't be able to, in theory they should be sort of too small to get along the string.

Geoff Brumfiel: So, I understand that there's been some debate over the details of this theory and now we have a new paper out this week in Nature by Haitao Liu and Philippe Lalanne of Paris South University. Tell me a little about what they've done.

Philip Ball: Well, they've taken a new approach to trying to understand what's going on. So previously, as I said, there was this idea that the light waves were exciting the electron waves and it's a little bit like looking at it from a distance and seeing these waves get excited. What these people have done is to zero-in on the tiny details of what's happening there, so instead of thinking in terms of electrons vibrating in waves, they thought "well what does an individual electron see when it gets excited by the light wave, how does it then behave." So basically what that means is they sort of considering the electrons one by one moving around on the surface and encountering these holes, and these holes are little bit like posts that scatter the electrons, they sort of go bouncing off, so they've had to consider how individual electrons are scattered by the little holes running through the metal and so they've built up a picture of what's going on sort of starting from that microscopic basis, that sort of electron by electron basis and that allows them to get a more detailed picture than we've had previously. So, they've been able to resolve some of the debates that had been going on about precisely what's going on here, but in essence it shows that the traditional picture of these electron waves -- the surface waves getting through the holes that that seems to basically be what's going on.

Geoff Brumfiel: So you mentioned earlier that people are actually interested in using this somehow, I am curious what sorts of applications people have in mind.

Philip Ball: Well one of the exciting things about the discovery was that it suggests ways of being able to move light around on chips. So instead of moving electrons round in little wires like we have on silicon chips at the moment, people are interested in doing this with light. There are various reasons why it might be more efficient to shift information around, shift signals around using light, sending it down little light wires, bit like fibre-optic cables, but the problem with that is that the cables can't be too small, because if they are then you run up against its effect, that the wavelength of light is too big to get down the cables, but if you can somehow have this sort of inter conversion of light and these surface electron ripples that allows you to effectively, sort of, do these manipulations with light, you sort of feed light in one end and its sets of these little ripples and they can go down through tiny, tiny channels that light itself couldn't fit down and then at the other end, they can sort of re-radiate the light. So, it sort of raises the possibility of doing all the sort of chip-based information processing, effectively using light, but actually on the chip itself, using these electron waves.

Geoff Brumfiel: Interesting. Okay Phil, well thanks very much for being with us.

Philip Ball: My pleasure.

Adam Rutherford: Nature's Phil Ball talking to Geoff.


Adam Rutherford: You are listening to the Nature Podcast. Coming up later in the show Mike Hopkin learns about the washroom in the sky, that's the air over the Amazon rain forest.

Kerri Smith: But first, a plant pathogen that could provide a new way to combat cancer. Bacteria are selfish and ruthless and they think nothing of hijacking useful pieces of the cells they infect and using them for their own game. Researchers studying a bacterium that infects plants have found a reason for its potency. They've discovered a compound called syringolin A or SylA that shuts down the cell's garbage disposal machinery, the proteasome. Without the proteasome, the cells can't get rid of unwanted proteins and fall foul to infection. Not only is this compound a novel find, but its proteasome -squashing powers could even be useful for targeting cancer cells. Lead author, Robert Dudler of the Institute of Plant Biology at the University of Zurich puts his team's discovery in context. Nature 452, 755–758 (10 April 2008)

Robert Dudler: It has been known that plant protein degradation machinery called, proteasome, which is involved in huge variety of cellular process in plants, is actually used by plant pathogens for their own purposes, for example, some virulence factors have been shown to target host proteins important for host defences for destruction. Now what we have here is sort of the opposite. The host proteasome is actually inhibited and we observe that this hampers defence of the plant, we assume that host proteins which are important for defence and which use the host proteasome, no longer can act.

Kerri Smith: So it is an inhibition rather than an activation?

Robert Dudler: Exactly! It is an inhibition of the host proteasome.

Kerri Smith: Moving on to SylA, I suppose itself then what's already known about this substance, syringolin A or SylA.

Robert Dudler: In collaboration with cancer research, we previously have done some experiments, which show that the compound not only can induce hypersensitive cell death or which is the foremost programmed cell death in plants, which we observed in plants, but also in human cancer cells and the reason we did these experiments were also of course, because it has long been known that inhibitors of the proteasome can induce apoptosis form of programmed cell death observed in mammalian cells and inhibit the division of cancer cells thereby and indeed proteasome inhibitors are a novel class of anticancer therapeutics.

Kerri Smith: But these proteasome inhibitors haven't been found in this bacterium or indeed in plant pathogens before.

Robert Dudler: No they have not. Of course, it's a unique compound, syringolin and we were able to clone the genes, which are responsible for the synthesis of this compound in the pathogen. Now the knowledge about the structure of these genes has allowed us to build a model about the biosynthesis of syringolin A, which is pretty unique. This in turn has allowed us to search through all known genomic sequences of the more than 700 bacteria, whose genome is completely sequenced, and we have found very similar gene architectures in three other bacteria, which we hypothesized to be able to synthesize similar compounds, which we believe, must be proteasome inhibitors.

Kerri Smith: So why is it that the cell isn't immediately killed when the proteasome stops working in this way?

Robert Dudler: Yes. The reason is that plants, as soon as their proteasomes are inhibited, start to re-synthesize novel ones. Now in cancer cells, of course, as you might assume, if you inhibit the proteasome, there are side effects and that's actually also the bad thing about this new class of drugs, may be of any class of drugs, that they have huge side effects and we hope that by synthesizing derivatives of this particular compound that we might alleviate these side effects to a certain degree.

Kerri Smith: The University of Zurich's, Robert Dudler. And now for our weekly opinion slots, the Podium. This week's speaker calls for a better and more international way to catch fraudsters. Here's Christine Boesz, Inspector General of the National Science Foundation, based in Arlington, Virginia

Christine Boesz: Headlines and surveys suggest that research misconduct is a growing problem. Has it increased or is it being detected and reported more often? Either way the International Research community must take notice. The fabrication or falsification of data, plagiarism, and general unethical behaviour damage both the scientists involved and the public's faith in the research that their taxes support. To preserve the public trust, countries, universities, and other research entities should have and should enforce formal policies and procedures for handling misconduct allegations. Many countries do have such policies, but many do not. Where they exist, differences within and between national policies create challenges in today's globalized world, where multinational cross-disciplinary research is common and desirable. So what happens when allegations are raised within international collaborations, which country or countries conduct the investigation and what happens when two relevant national policies are at odds? As international research becomes more prevalent, these seemingly theoretical questions are actually practical issues that must be resolved, fairly and objectively. The global science forum of OECD is addressing these issues. At the inaugural meeting of its coordinating committee for facilitating international research misconduct investigations last December, 16 participants representing 14 countries and international bodies engaged in 2 days of discussion about international research misconduct investigations. I represented the United States. We discussed sharing information, establishing networks, cooperation in dealing with allegations, and developing generic models of misconduct related documents. We agreed that harmonizing the research misconduct systems of different countries is unlikely and undesirable, given each nation's unique legal and administrative systems. Instead we chose to find a practical set of principles, directly relevant to international research misconduct investigations. We zeroed-in on the need for a central database of national research misconduct policies and for contact details for those responsible for investigations and we suggested that international agreements should include a general statement of the value of research integrity and recommendations of what to do if and when an allegation is made. The next meeting of the committee will take place in Paris in April. We will be discussing in more detail the principles of international investigations and how to harmonize national differences. In a perfect world, the committee's work would never need implementation; in a perfect world, research misconduct would not be front page news; until then we must continue to focus on creating a practical framework for examining allegations and holding researchers accountable for the integrity of their research.

Adam Rutherford: That was Christine Boesz on the Podium. Finally this week, Mike Hopkin breathes in nice, clean Amazonian air.

Michael Hopkin: Tropical rain forests are described as The World's Lungs. Chemical reactions inside the billions of plants keep our atmosphere supplied with oxygen, but the oxygen-rich chemistry of the rain forests also helps to remove pollutants, effectively scrubbing the air clean above the forest, and now a new sampling study of the air over the Amazon, shows that this cleaning capacity is even more extensive than we thought. Underlining once again, the vital importance of preserving the world's rain forests. Jos Lelieveld of the Max Planck Institute for Chemistry told me about the new research. Nature 452, 737–740 (10 April 2008)

Jos Lelieveld: By my making use of aircraft measurements over the Amazon forests we found that the oxidizing capacity and that is, sort of, the cleaning capacity of the natural atmosphere over the forest is much larger than anticipated. Previously it was though that the capacity of the atmosphere to remove gases that are emitted from natural resources, but also from pollutant sources was much less.

Michael Hopkin: I see, you mentioned pollutants there. I mean, is that why this cleaning capacity of the rain forest is so important?

Jos Lelieveld: The importance of the Amazon is that it is in the tropic, where the natural capacity of the atmosphere to clean itself is highest in the world and many of the gases actually that are emitted at high latitudes, like methane or carbon monoxide, are being broken down in the tropic, so one can see the tropics, sort of, as the washroom of the atmosphere and therefore its very important to understand how these processes are regulated in order to be able to estimate how future developments might influence the atmospheres.

Michael Hopkin: In simple terms then, you go easy on as here, but how does this chemical cleaning of the atmosphere actually work?

Jos Lelieveld: Yeah. Well, you probably are aware that in our atmosphere we have about 20% oxygen, and because of this oxygen our atmosphere is rather unique that it is so oxidizing and that helps us also to clean the atmosphere from pollutants. This is done through a number of steps. It is not the oxygen itself that reacts with these pollutants and these gases that are being set free by force. We first have to make ozone and from the ozone when the sun is shining you can make hydroxyl radicals and these radicals are very reactive compounds that oxidize the pollutants that are being emitted from the surface and if you do this in polluted air, you can get a situation where you have a lot of ozone and a lot of oxidants, which is a toxic situation, but if you then look at the Amazon atmosphere, the natural atmosphere, the cleaning capacity of the natural atmosphere is much more efficient actually in removing all these compounds and do not lead to by-products that are undesirable, as we see in polluted air over Europe and United States for example in summer.

Michael Hopkin: So bearing that in mind, what would be the likely effect of the continuing deforestation that the Amazon basin is facing?

Jos Lelieveld: Yeah. That's our big worry because we see that there is a nice balance between the huge amounts of hydrocarbons that the forests are releasing into the atmosphere and the removal of these gases from the atmosphere in the natural environment. So we see a very very interesting and very well established balance between what the forest releases into the atmosphere and how these compounds are being removed. Now if you remove the forest and you replace them for example, you know, we put cattle there or you have active agriculture or urban environment or industry, then you'll see that there are many other compounds being emitted into the atmosphere that disturb the balance and produce a lot of ozone.

Michael Hopkin: What does that mean, you know, for places that might suffer from ozone or nitrogen pollution. I mean if the forests were chopped down, and those compounds were emitted there, you know, will that worsen our own pollution in urban areas?

Jos Lelieveld: What will happen is that in the areas where the forests are being cut and being replaced by stronger pollutant sources, we will see that locally we will have very strong production of pollutant ozone, but this is of course also transported into the atmosphere and especially when it is transported upward, it has a very strong climate effect also, so it contributes to climate warming.

Michael Hopkin: I see. So, it's yet another example where the overall global problem, lets say, will be one of global warming.

Jos Lelieveld: Yeah, that's certainly something that will contribute to it. What we've seen here is really a very nice example of, if we leave it alone, then we see that the system is very well in balance and that it regulates itself and as soon as we start interfering with it and staring to put in pollutant gases, and mixing them up with the natural environment, we see that we immediately will get detrimental levels of ozone being built up there.

Michael Hopkin: I mean, in a way that's a message that a lot of forest conservationists and geochemists have been telling us for a long time, I mean, what to your mind is the most exciting part of your research?

Jos Lelieveld: Yeah! The exciting thing that we have discovered here is really in the chemistry because we know that the forest is releasing a huge amount of gases, in particular, isoprene into the atmosphere and the amount is really huge. On a global scale, we are talking about something like 500 million tons are so per year, its really a large amount and this chemistry now we've looked at in a little bit more detail and we are now seeing that our recycling mechanisms in the atmospheric chemistry that actually provide this much better balance between how the atmosphere and the forest interact than we have thought previously.

Adam Rutherford: Jos Lelieveld there. That's all from us. We play out with science hip-hop for the second week running! Who knew it is such a popular genre?

Kerri Smith: This week's Sound of Science comes from a musical stage show called FMA Live! Named for Newton's Second Law of Motion which of course is force equals mass times acceleration. FMA Live!, sponsored by Honeywell and NASA, is currently on a 12-week tour of the US bringing hip-hop science to 20,000 students. I'm Kerri Smith.

Adam Rutherford: And I am Adam Rutherford. Thanks for listening.

[Sound of Science Plays]


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