Nature Podcast 16 November 2006

Introduction

This is a transcript of the 16 November edition of the weekly Nature Podcast. Audio files for the current show and archive episodes can be accessed from the Nature Podcast index page (http://www.nature.com/nature/podcast), which also contains details on how to subscribe to the Nature Podcast for FREE, and has troubleshooting top-tips. Send us your feedback to mailto:podcast@nature.com

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Chris Smith: This week, new hope for muscular dystrophy, thanks to a breakthrough by scientists in Italy.

Giulio Cossu: We treated dogs that are affected by muscular dystrophy by injection of donor stem cell and could find they recover motility in this animal.

Chris Smith: Researchers have also pinpointed a way to heal a broken heart.

Paul Riley: The fact we've identified can actually promote the movement of cells from the outer layer of the adult heart into the muscle of the heart to form new blood vessels and repair damage from heart disease.

Chris Smith: And a milestone is reached in sequencing the Neanderthal genome, one million genetic letters to far.

Ed Green: This is just a first step in our ultimate goal of cloning Neanderthal and making a Neanderthal army.

Chris Smith: There'll be more from Ed Green, coming up later. Hello, I'm Chris Smith. Welcome to this week's Nature Podcast. Now, as we've just heard, scientists in Italy have taken a big step forward in the treatment of muscular dystrophy, which is an inherited muscle wasting disorder caused by a mutation in a muscle protein called dystrophin. In trying to treat the condition previous efforts have focussed largely on attempting to deliver a healthy copy of the faulty gene. But now Giulio Cossu and his colleagues have taken a different approach, they've isolated a population of stem cells called mesoangioblasts which would normally produce muscle cells in the walls of blood vessels, but if cells from healthy dogs are injected into the blood stream of dogs with the canine equivalent of muscular dystrophy, they migrate into and replace muscle tissue which has been damaged by the disease. Nature advance online publication 15 November 2006

Giulio Cossu: We tried a new protocol of cell therapy in dogs affected by muscular dystrophy and we transplanted normal stem cell into the arteries of these dogs and after five injections we noticed that these dogs had preserved and sometimes improved walking ability.

Chris Smith: What sort of stem cells did you use in the therapy?

Giulio Cossu: These are stem cells that are associated with the blood vessel and we name mesoangioblast.

Chris Smith: So how do they actually work to improve muscle function in these dogs that are, under normal circumstances, destined to get this disease?

Giulio Cossu: These cells can cross the vessel wall, enter the area where muscle is regenerating and being incorporated into new muscle fibres. Because they're normal, they contribute the normal copy of the gene that is missing in muscular dystrophy, in this case dystrophin, and fibres newly formed have force of contraction that is normal and overall the dog recovers a significant motility.

Chris Smith: Now you mention that you derive these stem cells from blood vessels, so that would presumably mean that they were destined to become smooth muscle, so how does it end up that these cells become striated, skeletal muscle once you inject them?

Giulio Cossu: As long as the cells remain in the vessel wall, they tend to become smooth muscle, which is their natural fate, but we have noticed cells that, in vivo, tend to leave the vessel wall and they enter the tissue where the vessel is. so if this tissue is skeletal muscle these cells have the ability to adopt a different fate and being recruited to a skeletal myogenic fate and, thus, form new muscle fibres.

Chris Smith: How long does the effect last for?

Giulio Cossu: Well, we do not know. We kept the dogs under observation for more than one year and they were still fine, but we have no data on longer periods.

Chris Smith: Now one of the other tissues that gets quite profoundly affected by muscular dystrophy but also by a range of other diseases is the heart. Did these stem cells also migrate into cardiac tissue and exert repair effects there?

Giulio Cossu: Not really. These cells migrate into the heart tissue with low efficiency and they differentiate very poorly into new cardiomyocytes. So, at present, it would not be possible to envision a therapy for the heart with the same cells.

Chris Smith: Giulio Cossu from Milan's San Raffaele Scientific Institute describing how he's managed to rescue dogs with muscular dystrophy using a population of mesoangioblasts stem cells. Now, indecently, it's a good job that medical authorities in Italy are a bit more relaxed about mobile telephones on hospital wards because Giulio joined me for that interview from his hospital bed where he's currently awaiting surgery to correct one or two broken bones, so we wish you a speedy recovery Giulio. Now although those mesoangioblasts were not very effective at repairing cardiac tissue, by studying how the heart develops in the first place, UCLs Paul Riley has uncovered a key protein called thymosin beta-4 which mobilises blood vessel forming cells from the surface layer of the heart, which is known as the epicardium and now it turns out that this molecule can work in adults too. Nature advance online publication 15 November 2006

Paul Riley: The problem is that the heart can't repair itself so if heart disease or damage occurs then there's no means, at the moment, of the heart actually repairing the damage, be it in the muscle or the blood vessels or otherwise. So what we're trying to do, really, is to get an idea of can we find cells within the heart that we can stimulate or factors that can stimulate those cells to try and initiate repair following damage and heart disease.

Chris Smith: So what sort of strategies are you coming up with to try and surmount the block?

Paul Riley: Well, what we've been doing is we've been looking at certain factors and proteins, really, in their role in heart development and, in doing that, we've found a protein that seems to also stimulate adult cells as well.

Chris Smith: So what the idea here is to recapitulate what's going on when the heart builds itself in the first place to try and make it rebuild itself?

Paul Riley: That's exactly right and we think that proteins and factors that are very important for the developing heart and how it actually forms initially could be translated across in terms of a function in the adult and actually trigger adult cells which are thought to be at rest, if you like, back to their more developmental type.

Chris Smith: And what are the actual factors that you've homed in on?

Paul Riley: Well the fact that we've homed in on is called thymosin beta-4 and it's basically a protein that binds to a major component of the cell skeleton, if you like, called actin and it's involved in cell movement and we've then gone on to find that it also functions to promote cell movement in the adult heart.

Chris Smith: So just talk us through what you actually did and what you've found so far.

Paul Riley: Okay, well we knocked down this protein, thymosin beta 4, using RNA interference in the developing mouse heart and we found that when we did that there was a problem with the vessel development in the heart and that caused the surrounding muscle to appear damaged and dying and what we then discovered was that what was happening was the outer layer of the heart, called the epicardium, was failing to provide cells that can move inward into the muscle and form new blood vessels. And without new blood vessels the heart fails to be nourished and sustained with nutrients and oxygen. We then made a huge leap of faith and asked the question whether this could work in an adult situation and have this protein acting on the epicardium to promote these cells to move inward into the muscle and form new blood vessels.

Chris Smith: And did it work, when you added the factor to the adult?

Paul Riley: Yes, to our great surprise it did. We took small pieces of this outer layer of tissue and put them into a tissue culture dish. When we had them on their own nothing happened in our usual media but when we added this factor, thymosin beta 4, we got extensive movement of cells from this layer of tissue into other areas in the dish and then we were able to have a look at those cells more closely and we determined that they were, in fact, cells that could make up healthy blood vessels.

Chris Smith: But blood vessels are one thing but, of course, the thing that people who've had a myocardial infarction, a heart attack, are lacking are the actual cardiac myocytes so are you saying that this factor could be used as part of a two-pronged approach, you might give this factor to boost the vascularity of the heart and then provide some additional heart cells to replace those that have been killed in the meantime?

Paul Riley: That's absolutely correct, I mean, this is limited at the moment in terms of it's application, purely to forming new vessels in a situation following damage and you are quite right, the muscle loss would have to be replaced by other strategies. So this would be exactly that, a two-pronged approach whereby some other source of muscle cells, or cells that could form muscle to repair the damage, would be accompanied by treatment, say, with something like thymosin beta 4 which could promote this new vessel growth that's required.

Chris Smith: Paul Riley from University College London, with a new way to mend a broken heart. Not using flowers or chocolates but with thymosin beta 4 which stimulates the formation of new blood vessels. Coming up shortly a taste of synaesthesia, the Neanderthal genome project and an incredible Palaeolithic burial site containing two newborn infants locked in each other's arms. First though, to the even more sombre spectre of avian flu which is hovering on the horizon. Human flu pandemics occur roughly every 30 years and they involve the jump of a bird strain of the virus into humans. At the moment the best contender for the next flu pandemic strain is H5N1 but what's it take to turn bird flu into man flu? To find out I caught up with Mill Hill's John Skehel. Nature 444, 378–382 (16 November 2006)

John Skehel: We're describing some mutations in the haemoglutanin of H5N1 influenza which result in the haemoglutanin being able to recognise human receptors as well as avian receptors.

Chris Smith: So what would have to happen for the virus to begin to transit between humans and how do you think that occurs then?

John Skehel: Well, it has to be able to bind to human receptors better than it does when it's just an avian virus and how that's happened in the past is a couple of mutations in the receptor binding site of the haemoglutanin occurred which allowed the thing to recognise human receptors as opposed to avian receptors. So the idea is that similar mutations are going to have to happen in the H5 haemoglutanin if it's ever going to pass efficiently between humans.

Chris Smith: And is that what you found?

John Skehel: So what's been done in this paper, largely by our Japanese colleagues, is that they've taken the H5 viruses and they've looked for viruses in those collections, by cloning the viruses, to see if there are any which are able to recognise human receptors and they found three viruses out of 21 that they looked at, that were able to recognise human receptors and also recognise avian receptors.

Chris Smith: Were there any consistent genetic changes in those viruses that consistently recognised human receptors as well as bird forms?

John Skehel: Yes, when they cloned them and identified what they bound to, they then sequenced the haemoglutanins and found about six mutations, two of which were in the receptor binding site and when they rebuilt viruses containing haemoglutanin that they'd put these mutations in, they found that the ability to bind to the human receptor correlated with either one or both of these mutations.

Chris Smith: And, as well as that, if you actually look at the structure and the model of H5N1s, the HA, the haemoglutanin, are changes in those amino acids... are they consistent with an ability of the receptor to recognise a different surface molecule?

John Skehel: We solved the structure of the wild type haemoglutanin that they'd introduced the mutations into and what we could see from that is that these two changes, our impositions were it would make sense for them to influence receptor binding specificity.

Chris Smith: So does this mean, then, that we, potentially with this work, have some kind of handle on determining whether or not a virus is going down the pathway towards being able to have a human tropism?

John Skehel: I mean, that's the hope, the extension of that is to increase surveillance to see if we can find more of them like that.

Chris Smith: John Skehel from the National Institute for Medical Research at Mill Hill, describing how he and his colleagues have pinpointed two key changes in the genome that seem to be necessary and sufficient for bird flu to jump out of the bird world and into the human population. Now, on a more colourful note, to synaesthesia, quite literally the mixing of the senses. Nature's Jim Giles has been finding out what it's all about.

Lynette Kay: The colours and the shapes are the main components of what I see and they always come in from the left, the left-hand side. I don't sit with my eyes closed, as soon as the music starts it just happens and the shapes move continuously towards the right. They might rise, they might stay there, they might disappear and the shapes will have an ethereal quality to them which I literally do not have the words to describe them, which is perhaps why I paint them.

Jim Giles: That was artist Lynette Kay describing who she's using the foxtrot from Shostakovich's Jazz Waltz as an inspiration for her paintings. Lynette is a synaesthete and her condition greatly interests neuroscientists.

David Eagleman: Synesthesia is a harmless, perceptual condition where there's a mixture of the senses. So, for example, somebody might hear music and they see colours, they actually experience the colours. A very common form is where people see letters of the alphabet in colour, so when you show them the letter M, even thought it's with black ink that, for them, will trigger the experience of, let's say, purple. It's not a hallucination, they don't actually think the ink is purple but it triggers an experience of purple and it's involuntary and automatic. It can actually be any mixture of any of the sense so, for example, some people might, when they are touched, they will get a taste in their mouth or when they hear something that will trigger a smell for them and these are not memorised associations but actual physical experiences.

Jim Giles: David Eagleman of Texas University. He presented his research on uncovering the genetic basis of synaesthesia at a neuroscience conference last month. http://blogs.nature.com/news/blog/2006/10/do_you_have_synesthesia.html

David Eagleman: What I've done is collected up large family trees where synaesthesia is running through the tree and I follow the trait through the family tree and I look at the genes that are going that way too and what I've now found is a hotspot on chromosome 16 and what we're working on now, we've now found the region of the genome where the synaesthesia gene lies and now we're working on sequencing it so we find exactly what that gene is.

Jim Giles: So we're getting closer to finding a gene, when we do what sort of function can we expect it to have?

David Eagleman: There are two theories about what might be causing synaesthesia, one of them is that you actually have more physical wiring in the brain of a synaesthete, so let's say their hearing and their colour areas are more tightly wired to each other. The alternative theory, which I favour, is that the wiring is the same in everybody but with a synasethetic brain the balance of inhibition is a little bit different and, as a result, they get to experience those cross modal connections. So in all normal brains, parts of your brain that care about hearing and those that care about vision, are heavily interconnected, it's just that you're not normally aware of those connections, those can be unmasked if you blindfold yourself for five days and then all of a sudden your visual cortex is involved in hearing and in touch and things like that.

Jim Giles: So it's actually less a case of crossed wires than uninhibited brain connections but what's it actually like for people who have it? It turns out to have its good and bad sides.

Lynette Kay: I love having it, I mean, obviously because it's quite fun experiencing the colours, it's lovely. The drawbacks really are that you can't go to a concert if there are particular, for instance, Radiohead is one thing that I've actually had to get the car stopped and get out of the car because it was so bad and that continued, the effects of the music with Radiohead continued for 24 hours. If you think back to the 60s and the psychedelic effects that they were showing us from the effects of LSD, that's exactly what I experienced.

Jim Giles: Just like Lynette, most synaesthetes wouldn't want to give up their condition. In fact, it can even have some advantages. David Eagleman again.

David Eagleman: If you're synaesthetic and I ask you to remember my phone number, the sequence of numbers will have a certain colour pattern and that might make it easier for you to remember so, typically, synaesthetes are slightly better at memorising sequences of numbers and things like that. Otherwise there's no real advantage. Again, since we all accept the reality presented to us, my reality seems perfectly fine and theirs seem perfectly fine to them. A synaesthete would not want to give that up, just like you wouldn't want to give up your sense of smell because you are already used to it.

Chris Smith: Synaesthesia, it seems something you wouldn't sacrifice readily. It's also like saying you'd give your right arm to be ambidextrous. That was Nature's Jim Giles.This is Nature's podcast from the 16th November edition of Nature with me, Chris Smith. And now to Austria and a unique insight into the lives of our ancient relatives because Christine Neugebauer-Maresch and Maria Teschler have found the pristine remains of a pair of infants, possibly twins, lying in each other's arms. Nature 444, 285 (16 November 2006)

Christine Neugebauer-Maresch: We had good luck to find three burials of infants with an age about 27,000 years from excavations at Krems in the centre of lower Austria. The very important thing in this case, it is newborn children and very rare, these are really complete burials and in this position they were never found.

Chris Smith: And how were the bodies of the newborns discovered?

Christine Neugebauer-Maresch: There is an excellently preserved cultural layer in a depth of about six meters and below these cultural layers was a mammoth shoulder blade found and this shoulder blade covered a small pit which was filled up with red ochre and in that were the two babies.

Chris Smith: So what do you think the significance of the red ochre that was covering the children was?

Christine Neugebauer-Maresch: We don't really know this but the use of red ochre in connection with graves and burials is common in the Stone Age. In this case maybe it's a symbol for life, the red colour.

Chris Smith: Were the bodies bearing any other kinds of ornaments or other things that were packed in their graves with them?

Christine Neugebauer-Maresch: Yes, more than 25 or 30 ivory beads was aside one skeleton.

Chris Smith: And looking at the big picture of where humans were in this period, in this area geographically, how does this fit in with our understanding of who these people were and what they were doing?

Christine Neugebauer-Maresch: In this area we know from our excavations that there were people and they were hunters and gatherers between 40,000 and 27,000 years before today.

Chris Smith: Just turning now to Maria Teschler, who is a co-author on this paper, and also an anthropologist, Maria, when you examined these skeletons do we know why these newborns ended up being buried, what killed them, do we know?

Maria Teschler: At the moment we cannot answer this question. we know that these individuals are newborns, there was some tooth remains preserved and we could identify the age of death of these newborns and at the moment there is no concrete answer on why they died. I could not recognise any feature any pathologic feature, a fracture or other pathologic signs. But we suggest that these individuals are twins because they have the same dimensions of long bones and having twins in that time could be combined with problems at the birth.

Chris Smith: Returning to you, Christine, what are the implications for having found this burial of newborns?

Christine Neugebauer-Maresch: The burials are important because they are very rare, burials of the Palaeolithic and the skeletons of Palaeolithic in Europe and those recently discovered in some burials, they were covered with red ochre and decorated with ornaments and they imply that they are really deliberate burials associated with a ritual. This says to us that even newborns were considered full members of hunter-gatherer communities.

Chris Smith: Christine Neugebauer-Maresch from the Austrian Academy of Sciences and Maria Teschler from the Natural History Museum in Vienna, who have found the remains of several infants dating back over 27,000 years. They prove that, even that long ago, infants were judged to be every bit as important as other members of their tribe. And sticking with people from the past, we finish this week on a very high note because researchers have now successfully sequenced a million genetic letters of the Neanderthal genetic code. Edward Green, talk me through it. Nature 444, 275–276 (16 November 2006) ; Nature 444, 330–336 (16 November 2006)

Ed Green: We have recovered sequence from 38,000-year-old Neanderthal fossil, from a cave in Vindija, Croatia and we have sequenced the DNAs we recovered from this fossil and are starting, now, a Neanderthal genome sequencing project.

Chris Smith: I don't want to be devil's advocate too much, but how do you actually know it's Neanderthal DNA and not, say, some other hapless human or even an archaeologist that's contaminated it?

Ed Green: That's a good question. So it turns out that most fossils that one examines for DNA, one can find modern human DNA contaminating it and, basically, the first thing that we had to determine was can we find a fossil that has little or no contaminating modern, human DNA on it? For this we have an assay using primer pairs that flank mitochondrial hypervariable region that differs from all Neanderthals that had been sequenced to date and all humans that had been sequenced to date, so this is the basis for an assay, one can extract DNA from a fossil, amplify in an unbiased way, whatever hypervariable region sequences are there and then count to see how many are human and how many are Neanderthal and from this you can tell how contaminated your fossil is.

Chris Smith: What's the overall quality of the DNA that you get out from a 38,000-year-old piece of Neanderthal?

Ed Green: Well, as you might imagine, it is not very good. Lots of defragments are less than 100 nucleotides long and also what we can see is that a lot of the cytosine has been deaminated and we then read that through the PCR and sequencing as a thymidine, so we see this huge access of C to T mutations when you compare Neanderthal to human.

Chris Smith: And when you look at the Neanderthal sequence, though, what does that tell us about our relationship to them?

Ed Green: Well, this is a good question, it might not be a question that can be answered very quickly but one thing that it tells us, that we obviously suspected already, is they're very closely related to us. And what we would like to do with the sequence now is not so much answer questions about what Neanderthals were like and what their phenotype was, but rather use this Neanderthal sequence to annotate the human genome. And this is important because we have the chimpanzee genome and we have the human genome and we can find all of the differences between those two and there are roughly 35 million differences there, but we can't now determine when all of the changes that are specific to the human lineage happened, but now with the Neanderthal we can ask for any genetic difference, when did it happen? And the ones that happened after humans split from Neanderthal are very interesting because it's this period of time when modern humans emerged with their advanced culture and language and all of the things that set modern humans apart from all of the hominids that preceded them.

Chris Smith: Now a big question about Neanderthal evolution is where they actually went at the end, because some people say they just died out, others say well, was there some kind of inter-mixing phenomenon, are there any clues in the genome from that, because 38,000 years is obviously quite close to their end?

Ed Green: Well, we can't say for sure, with the amount of sequenced data we have now but in the near future as we expand this project to get more and more sequence, we should be able to say, with some confidence, whether there was gene flow from Neanderthal into modern humans but we also would like to answer the question that has been largely ignored and that is was there gene flow from modern humans into Neanderthal? And we really have no great answer for either one of these, but as more and more sequence data comes in and as we get closer to our goal of one full coverage of the Neanderthal genome we should have a very good answer for this question.

Chris Smith: Ed Green from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, kicking off the Neanderthal Genome Project. Well, that's it for this week and thank you very much for listening. I hope you'll join me next time when I'll be exploring the reasons behind some gaping holes in the human genome. In the meantime, don't forget that if you want to find out a bit more about any of the reports in this week's programme, they're all available from our website which is http://www.nature.com/nature and if you'd like to send us any feedback, the address is mailto:podcast@nature.com. If you're in the mood for some more acoustic stimulation, this week's edition of the Naked Scientists podcast explores the science of sound, including the maths of music and the geometry of jazz. That's the Naked Scientists podcast which is freely available from http://www.nakedscientists.com. This show was produced by me, Chris Smith, with Anna Lacy and Fran Beckerleg. Until next time, goodbye.