Nature Podcast

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Kerri Smith: This week, the Origin of Species; we plunge into Lake Victoria to find out how site and stripes joined evolution.

Adam Rutherford: And how some old wax-encased tissue samples hint at the life story of HIV.

Michael Worobey: The idea is to kind of use them as a time machine to get tissue blocks that go back several decades, pull DNA from HIV out of them and then analyze the sequences.

Adam Rutherford: This is the Nature Podcast. I'm Adam Rutherford.

Kerri Smith: And I'm Kerri Smith. First this week, we're entering the microscopic, but well-populated world of RNA. RNA acts as the messenger for DNA, which encodes proteins, but just as you might write a story and then edit the text, several other forms of RNA edit this original RNA message, spotting and correcting errors and turning genes ON and OFF. One type is microRNA. Researchers thought that many of these microRNA molecules were pretty much unique to more complex animals, but a team has now found a bunch of microRNAs in simple creatures including sea anemones and sponges. I called co-author Andrew Grimson of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts and he gave me some background. Nature advance online publication (1 October 2008) doi:

Andrew Grimson: MicroRNA's they really were only discovered in animals about 15 years ago, and so what it turns out that they do is that they probably their majority of their function is to subtly regulate the amount of expression that comes from an mRNA, so an mRNA messenger RNA is an intermediary in how our genes are expressed into functional molecules.

Kerri Smith: But they've only been identified in certain organisms so far, is that right?

Andrew Grimson: Right. So, they've really only been studied or almost exclusively only been studied in what we referred to as bilaterian animals, so bilaterians really include most animals that we think about, they include mammals, they include flies, they include worms and what we wanted to do in this study was to look at much earlier diverging, so much more ancient relatives of the bilaterians and ask the question whether or not there are many microRNAs or indeed any microRNAs in these really ancient relatives of bilaterians.

Kerri Smith: And which relatives did you home in upon?

Andrew Grimson: The first we looked at is the sea anemone, which is known as Nematostella vectensis. That's a reasonably close relative to bilaterians. We then also looked at Trichoplax adhaerans, which is a slightly more distant relative and then the most distant diverging animal that we looked at it is Amphimedon queenslandica, which is the sponge and what we did was to try and look and see what aspects of the smaller RNA biologies mostly microRNAs could we see in these relatives.

Kerri Smith: And so previously I guess it wasn't that we didn't think that microRNAs didn't exist in these animals, but no one had really gone and looked for them yet.

Andrew Grimson: So, all that had been done outside the bilaterians in animals was a couple of investigations, a couple of years ago, looking in Nematostella and these studies provided reasonably convincing evidence for the existence of a single microRNA in Nematostella.

Kerri Smith: So, microRNA has been found in Nematostella, that's the sea anemone before. So how have you added to this picture?

Andrew Grimson: So, the previous studies took existing bilaterian microRNAs and asked whether they could see the same microRNAs in Nematostella. The drawback to that approach was that they weren't able to find microRNAs that were specific to Nematostella and so the approach that we took was a very different experimental strategy, which was not biased by looking for relatives of known microRNAs. So we systematically tried to identify any and hopefully all microRNAs within Nematostella.

Kerri Smith: So how did you go about finding these microRNAs then, because usually if you're trying to compare sequences, you know, you have to have a pretty decent sized chunk of sequence?

Andrew Grimson: Sure, so what we did was we took advantage of reasonably new technologies, these are known as high-throughput sequencing technologies, where you can take a sample of an organism and you can generate a very large set of sequences that correspond to whatever biological nucleic acids you are interested in, in our case, small RNAs, so we generated millions of different sequences from each of these organisms and then by looking at these sequences, we can look for patterns that are highly diagnostic of microRNAs.

Kerri Smith: I see and what was the outcome then?

Andrew Grimson: What we found in Nematostella was that we found is there at least 40 different microRNAs in Nematostella and only one of them is related to any of the bilaterian microRNAs. So it seems like Nematostella during the evolution of this lineage required a lot of different microRNAs and probably the microRNAs in Nematostella are probably regulating very different pathways than the bilaterian microRNAs targets.

Kerri Smith: So they're really sort of a completely different species as to really put in the right word, but they're very different groups.

Andrew Grimson: They're definitely microRNAs and because there is one microRNA that is shared between Nematostella and bilaterian, we know that there is a common origin there, but during the divergence we're talking about hundreds and hundreds of millions of years, the microRNAs have diverged in sequence and therefore function.

Kerri Smith: So what else might the implications be then for our theories of what RNA does in different organisms and how it might contribute to may be organism complexity?

Andrew Grimson: So one idea that certainly people have not debated for a while is that perhaps the simplest animals may not have microRNAs and maybe that organismal complexity for example in the bilaterian could well have been facilitated by microRNAs but what we found is looking at one of the species in particular, this is the sponge Amphimedon, we did found microRNAs in Amphimedon, so even this one of the simplest of animals, has got microRNAs and so we shouldn't really think about microRNAs as being restricted to only more complex organisms.

Kerri Smith: Andrew Grimson there. Coming up later, a small of an ever device for measuring magnetic fields with implications for physics, material science, and biology plus we tackle the challenges of HIV.

Adam Rutherford: But first, there are many mechanisms that drive one species to split into two, for example when populations get isolated from each other by a lake forming or forest being cleared, plenty of evidence to support that idea, but there's one concept of how species form that has resided mostly in the realm of the theoretical. This is the idea that as individuals adapt to their environment, these adaptations may have a knock on effect on mate choice, a process called sensory drive speciation. Now an international team led by Ole Seehausen has waded into Lake Victoria in Africa and shown that this sensory drive speciation does occur in cichlid fish. They have shown that a female preference for either red or blue striped males only exist in clear water, where basically they can see. I spoke to Ole and started by asking him how they actually go fishing for data in the lake. Nature 455, 620–626 (2 October 2008)

Ole Seehausen: So, the fish are small; the males are about 2 times the size of the females and that's about 10-12 Centimetres. We collected them by setting gill nets under water. And where the water is clear enough the diver can go down and collect the fish from the nets and record exactly the water depth and the habitat structure where each fish was caught, where the water is very turbid, very murky, we can't go into the water and we wouldn't see anything so we have to do it from the boat, so we set the gill nets and then we pulled them up again after a while and record again for every stretch of mesh and fish that came out of it, what particular characteristics of that site were.

Adam Rutherford: It sounds like a lot of fun. So you've been looking at how species are being driven apart within the same location in different spots across Lake Victoria, so how is this working? What does your results show?

Ole Seehausen: Yeah, so these results show that where the water is relatively clear and the light gradient is gentle so light changes slowly as you go from the surface to deeper water, you find a very strong association between water depth and colour of the males, such that the blue males tend to sit in shallow water and the red males tend to sit in deep water; with a little bit of overlap but not much at all. Whereas, if the water becomes less clear and this gradient becomes deeper this distinction in the depth distribution of the two colours, kind of, collapses. So eventually if it is very turbid and the light changes rapidly, there is no difference between the red and the blue males in where they sit in the water column. So it appears as if where the gradient is gentle they can adopt both in the use of their colour that they use for signalling and in the visual system to the local environment when there is change in the local environment happens at very short distance in the water there is no room for adaptation to the specific environments.

Adam Rutherford: And alongside looking at actually where the fish are located you've also looked at some of the genes involved in at a molecular level.

Ole Seehausen: Yeah, so we looked at 3 classes of genes that we report in this paper. Two are opsin genes and one that seems to be the crucial one here is tuned to long wavelength light so reddish light. It appears that where this two, the red and blue type are differentiated and adapted to their particular light environment, the red one is fixed for an opsin visual gene that shifts its peak vision by about 50 nanometres towards the longer wavelength. Remember they live in the more red shift, at the longer wavelengths of the environment. We also looked at this short wavelength sensitive gene that absorbs at the opposite end of the light structure, so in the blue area. We see some differentiations, significant differentiation between the reds and the blues in that gene too but far left than in the other one and we don't exactly know what it means.

Adam Rutherford: Okay now alongside providing really important piece in the evolutionary jigsaw puzzle, your results also have an impact on conservation in Lake Victoria, can you explain how you have come to that?

Ole Seehausen: Yeah, so the lake has undergone anthropogenic Eutrophication very massively in the last 30-35 years. So that enrichment in nutrients suddenly becoming more productive and that is because there is a lot more agricultural run off. So fertilizers from the surrounding lands going into the lake; there is fairly large cities, very large cities and very dense populations all around the lake; so there was a lot of effluents coming from the urban areas, industry and this together has generated a situation where lot more phosphorous and other nutrients have gone into the lake then they were initially, so algae growth and bacteria growth has increased and the lake has just overall become a lot more productive but therefore also a lot more turbid and so we expect that these gradients that we have looked at here where in clear water, the change in the light is slow as you go from the surface to greater depths, but in turbid water it is very quick and it does not allow the coexistence of multiple species. We expect that many sites have actually in the last 25-30 years experienced shift from one regime where multiple species can coexist to the alternative regime where there is no coexistence is possible and this we think has contributed to the very dramatic and rapid collapse of species diversity that has been recorded in Lake Victoria.

Adam Rutherford: That was Ole Seehausen from the University of Bern, always nice to see a bit of evolution in action.

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Kerri Smith: Next, like some kind of tiny ruler, Geoff Brumfiel gets the measure of a very small magnetic field sensor described in a paper in Nature this week.

Geoff Brumfiel: Magnetometers as the name implies measure magnetic fields. They are used in all kinds of things, magnetic resonance imaging for example and there are a lot of different types of magnetometers out there on the market. So what makes this new one so special? Well for one thing it's made of diamond which is pretty classy, but even more important to physicists is, it is capable of ultrahigh resolution sensing at the nanoscale. I called up Mikhail Lukin of Harvard University to learn more about what this new magnetometer is good for. Nature 455, 644–647 (2 October 2008) doi:

Mikhail D. Lukin: Magnetometer is a device which basically detects magnetic fields, measures magnetic fields and one kind of discrete from the type that I saw once from some Italian physicist about you know why different magnetometers are suitable for different purposes. So what he said is that you know magnetometer is like a knife and you cannot use a knife which is designed to cut, you know parma prosciutto for cutting bread. So what this means is that different magnetometers are kind of suitable for different purposes.

Geoff Brumfiel: I understand you've basically developed a new kind of magnetometer here and it's based on diamond, is that right?

Mikhail D. Lukin: That's correct.

Geoff Brumfiel: So there's quite a number of magnetometers already out there, I mean, why develop another one. What was the reason to develop this particular technique?

Mikhail D. Lukin: The motivation for our work is as follows: The other existing magnetometers, some of them are exquisitely sensitive at typically, you know, quite large in size compared to say one micrometer and there exists a great need for having magnetic sensors which are much smaller than micrometer. This need is motivated by the desire to basically extend this technique of, you know, magnetic resonance imaging like you know MRI-type techniques to the nanoscale level. That is to say, for example if you want to, you know, have a magnetic resonance image of a single atom or a single molecule.

Geoff Brumfiel: And so you've used diamond for this.

Mikhail D. Lukin: Exactly. So basically, you know this motivation calls for developing totally new approaches to detect magnetic fields and what we have done is we've used single impurities in diamond, single magnetic impurities in diamond as such a kind of nanoscale magnetic sensor.

Geoff Brumfiel: And, I mean, tell me a little more about how that works. So you have an impurity in the diamond and then...

Mikhail D. Lukin: So we work with some special impurities in the diamond which are themselves like little magnets. So in particular this impurity in diamond has the so called electronic spin associated with that and what we have learned over the last few years is that this spin can be a very sensitive probe of its magnetic environment.

Geoff Brumfiel: Why use diamond?

Mikhail D. Lukin: The reason why we've used diamond is that, first of all we really wanted to make a sensor which is very small. So that is very challenging if you deal, for example, with isolated atoms. So basically instead of starting with isolated atom, we wanted to start with some kind of, you know, spin which is confined in a solid object.

Geoff Brumfiel: But surely there must be a solid object that's cheaper than a diamond.

Mikhail D. Lukin: Correct. So the diamond however turns out to be a kind of unique host for such unique, I would say impurity. So in particular this special impurity, this so called colour centre which we have used is essentially like a little artificial atom which is strapped in diamond and what is unique is that basically diamond can you know act as a host for such an impurity while perturbing it very little.

Geoff Brumfiel: So, what ultimately is this going to be used for?

Mikhail D. Lukin: So, I would say there are three areas where I anticipate that this kind of device will have a lot of impact. The first area is quantum information science, quantum computation and perhaps quantum communication. Our sensor can be used to detect basically single electronic or nucleus pills and you know one could think about encoding quantum information in such objects and perhaps even, you know, to kind of transfer this information. The second area is biology and biophysics. One of the holy grails of nuclear magnetic resonance imaging is to try to directly map the structure of complex biological molecules like complex proteins for example. In order to do that you have to detect signals from individual nuclear spins, so our sensor should be eventually capable to accomplish this longstanding task. The final area where this technique might really have a substantial impact is in the area of magnetic imaging associated with condensed matter physics and material science. So basically the ability of looking at magnetic impurities, for example, in some complex materials and being able to image them you know possibly all the way down at the atomic level might provide some really unique insights into how complex materials work.

Kerri Smith: Mikhail Lukin talking to Geoff and there is more physics in Nature's new documentary series, Missions in Space-Time. Five short films about life, the Universe and a Theory of Everything and of course the Large Hadron Collider. The first film is released on Friday 3rd of October, you can sign up in I-tunes or watch the films on http://www.nature.com.

Adam Rutherford: And we end the show this week with one of virology's biggest challenges, HIV. This week's Nature features several articles on the virus, its biology, its prevalence and how to fight it. In a moment we will be hearing from Charlotte Stoddart, about efforts to develop an HIV busting vaccine, but first Natasha Gilbert has been finding out about some old virus samples and what they can tell us about life story of HIV. Nature 455, 661–664 (2 October 2008)

Michael Worobey: Over the last several years, my lab has been developing methods to try to recover RNA and DNA from unusual sources. In this case paraffin-embedded tissue blocks and the idea is to kind of use them as a time machine to get tissue blocks that go back several decades, pull DNA from HIV out of them and then use evolutionary trees to analyze the sequences.

Natasha Gilbert: Can you tell us a little bit more about this paraffin-embedded strain?

Michael Worobey: Basically what it is is if you go to the doctor and the doctor thinks that it might be worth taking a biopsy of some tissue to have a pathologist look in to it. That tissue ends up getting fixed in a bunch of chemicals that kind of preserve the tissue and then embedded in a bit of wax, the revolution in molecular biology has meant that it's not possible to go back to some of these ancient, well relatively old samples and pull nucleic acids out of them which is pretty exciting.

Natasha Gilbert: And your sample came from a hospital in Western Africa?

Michael Worobey: Yeah, my sample was from a collection at the University of Kinshasa and I actually have a few co-authors, two of my co-authors actually work at the Department of Anatomy and Pathology that housed the samples.

Natasha Gilbert: Had no one thought to sort of go back to these hospital banks before and try and extract the samples?

Michael Worobey: Well, that's an interesting question and it's something that I think most people just assumed that you couldn't do this work with old paraffin-embedded samples that you would really need a frozen blood sample. So I tried to see if we could actually get some sequences out of these sorts of things and part of the build up to this paper with years and years of pretty thankless work in the lab to develop the methods to isolate DNA and RNA out of these things and get it to amplify which is no easy task.

Natasha Gilbert: Can you tell us what you did?

Michael Worobey: Sure, so there was a single sequence previously published from a frozen blood sample that originated in 1959. So that was our only glimpse back into the fairly deep past of this epidemic and so now that we have a 1960 sample, you could do some nice things in terms of comparing them against each other. Like I said, it's kind of like a time machine. It helps us step back to 1959, 1960 and from that vantage point to look back again a few more decades to when we think the epidemic originated.

Natasha Gilbert: So what does comparing the two viruses show you?

Michael Worobey: Well, the simplest thing that it shows you is if you just line them up base by base they differ something like 12% of their size. Now if you did that with HIV strains that you sampled from let's say all over Europe and North America today, you would not find any pairs of sequences circulating in that huge range that were that different and we know from previous work that the epidemic in Europe and North America is probably 40 years old or so. So that tells you that in 1959, 1960 in Kinshasa there was already degree of genetic divergence that outstrips what we see 40 years into the epidemic in North America. So it's a kind of direct snapshot of a long history of evolution of the virus in Central Africa.

Natasha Gilbert: What do your results tell you about the evolution of the virus since its origin?

Michael Worobey: It's almost a perfect coincidence in the timing of the most recent common ancestor of the AIDS epidemic and the first emergence of sizable towns and cities in the area. It's a really really strong suggestion that before there were large towns and cities, HIV if it crossed into humans didn't have the conditions necessary to create a chain of infections and it would just die out, but once the cities and towns emerged, that was kind of the ecological change from the human perspective that allowed the virus to get a toehold and start spreading in humans. I find it kind of exciting because if we are right about this, it means that basically human beings made some changes that took a virus that was not capable of becoming a human pathogen and turned it into one that was capable of becoming a human pathogen and I think we now need to start thinking about how can we change that landscape back to drive HIV extinct. If we do everything we can just to reduce the possibility of each infected host transmitting it to the next person, I think it is reasonable to talk of driving the virus to extinction even without a preventive vaccine.

Adam Rutherford: Michael Worobey there talking to Natasha.

Kerri Smith: Changing human habitats in order to defeat the virus might be one way to stop it in its tracks, but another means of attack is to equip humans themselves with the means to prevent infection. Charlotte has this report.

Charlotte Stoddart: The development of a safe and effective vaccine against HIV-1, the most virulent strain of the virus, will undoubtedly be a good way to control the worldwide AIDS pandemic. But despite substantial effort, a successful vaccine has so far eluded researchers. In this week's Nature, Harvard Medical School's Dan Barouch takes a look at the major hurdles currently facing the field. Dan explained to me why HIV is a particularly problematic virus when it comes to making vaccines. Nature 455, 613–619 (2 October 2008)

Dan H. Barouch: The challenges associated with the development of an HIV vaccine are really unprecedented in the history of vaccinology. First and foremost, the diversity of HIV is much greater than any other pathogen for which there has been an effective vaccine developed. The virus can also evade immune responses and there is no method that currently exists that can elicit broadly reactive neutralizing antibodies. So the challenges associated with developing an HIV vaccine are profound and unprecedented in the history of vaccinology.

Charlotte Stoddart: Given all these challenges then, have any HIV-1 vaccines reached the stage of clinical trials.

Dan H. Barouch: There have been two vaccine concepts that have completed efficacy trial testing in humans the first one was the VaxGen gp120 vaccine. The goal was to generate antibody responses against the surface envelope protein and this vaccine was shown to fail in phase III efficacy trials in 2003. The second vaccine that has completed efficacy trial testing was the Merck Adenovirus Serotype 5 or Ad5 vaccine expressing Gag, Pol and Nef. This vaccine aimed to induce T-cell responses and phase IIB efficacy trials were stopped in 2007 for failure to either prevent infection or reduce virus load following infection.

Charlotte Stoddart: So two clinical trials have failed then what are the big hurdles that have to be overcome before we can produce a vaccine that actually works?

Dan H. Barouch: Well, I think the failure of the Merck vaccine was clearly a setback and a disappointment to the field, but important lessons have already been learned from this study. It has allowed the field to reflect and recalibrate and adjust scientific priorities. So, there will be a need for substantial increased basic discovery research without slowing down preclinical studies in clinical trials.

Charlotte Stoddart: Now, in the review that you have written for Nature, you make some recommendations, so could talk us through some of those, what direction do you think the field needs to take now?

Dan H. Barouch: Well, I think the first recommendation that I have is that this no time to quit. There have been setbacks, there have clearly been disappointments in the field in the past year, but this is no time to quit. In fact, this is the time that the field needs to reaffirm our commitment to develop an HIV vaccine, given the enormity of the global health problem.

Charlotte Stoddart: Despite all the setbacks, do you think that scientists shouldn't be too dispirited and it is worth keeping on with the research?

Dan H. Barouch: Absolutely. Failed efficacy trials are fairly common in many fields. In the malaria field, in the cancer field, other fields and so the failure of the Merck efficacy trial last year should not be seen as the end of the field, in fact it is quite the opposite. We've learned substantial amounts from it and although with a little disappointment that field can and will continue to move forward.

Kerri Smith: Dan Barouch there. That's all for this week's show. Remember there is more info about all the papers we've covered at http://www.nature.com/nature including the HIV special and more shows available at http://www.nature.com/podcasts.

Adam Rutherford: Next week, we've got Noble news, malaria genetics and how much kids really know about physics. I'm Adam Rutherford

Kerri Smith: And I'm Kerri Smith. Gravity always wins.

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