Nature Podcast

This is a transcript of the 27th March 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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Adam Rutherford: Coming up this week, we meet the oldest European who hails from Spain.

Henry Gee: A very important part of the fossil find is the date, which is quite well constrained between 1.1 and 1.2 million years old.

Kerri Smith: And we turn the accepted theory of how RNA interference works on its head.

Jayakrishna Ambati: These types of drugs have a mechanism of action that is entirely different than what is purported to be.

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

Adam Rutherford: And I am Adam Rutherford. First up this week, a puzzle over how RNA interference – the idea that genes can be silenced using RNA actually works. A study in Nature goes against the current accepted theory. Mike Hopkin found out more.

Michael Hopkin: Age-related macular degeneration is an eye disease that has inflicted blindness on millions of people worldwide. Researchers are hoping to cure the condition using a gene silencing method called RNA interference. But a paper published in this week's Nature shows that the effect may be more general than they had suspected. This might mean good news for sufferers, but it could also have serious implications for others users of the same gene silencing technology. I spoke to lead author Jayakrishna Ambati of the University of Kentucky and he began by telling me more about this surprisingly common disease. Nature advance online publication (26 March 2008).

Jayakrishna Ambati: Macular degeneration is in many ways a silent public health epidemic, not only throughout the developed world, but growingly even in developing nations, as living habits change. If one looks at the United States as an example, there are some 10 million people who have macular degeneration, which is greater than the number of people with all cancers combined and with the ageing of the population throughout the world, this burden will only increase in coming years.

Michael Hopkin: What exactly goes wrong with the eyes when this disease happens?

Jayakrishna Ambati: There are two flavours, if you will, of macular degeneration – the dry form which affects majority of people and in which the central vision is relatively intact at least in the early stages, the much more severe wet form of the disease, which affects 10 to 20% of people with this condition, is much more profound, it causes central vision loss and in some cases it can be so profound that it can lead to profound blindness and a change in the very way people have to function in their daily lives. In the dry form, it is as if someone took a pencil eraser and simply erased out some cells in the very centre of the retina, so called macula, and by erasing the function of these cells, we're no longer able to capture light and make out fine details. In the more severe, wet form, the problem is caused by the growth of blood vessels from underneath the retina and these blood vessels that leak fluid and blood and thereby cause tremendous anatomical and functional disturbance in the centre of the retina, which then leads to vision loss.

Michael Hopkin: How are people attempting to try and treat this disease?

Jayakrishna Ambati: The treatment of macular degeneration has been quite anaemic. There is a tremendous need for better and newer therapies for this condition, given the present state of affairs. In that light, the development of small interfering RNA or siRNA technology has promised to revolutionize the treatment of macular degeneration as well as that of a variety of other conditions, in which a single gene or a single protein can be targeted and work in mice has proved surprisingly predictive of efficacy of potential drugs in this condition, macular degeneration in humans.

Michael Hopkin: And how does your work on mice fit into this picture of these therapies that seem to be emerging now?

Jayakrishna Ambati: What we found is quite surprisingly that siRNAs don't actually work in the way that they are thought to function, that is, siRNAs are premised to work by a mechanism known as RNA interference, which incidentally was awarded the Nobel Prize two years ago. Instead we found that siRNAs don't work in this sequence-specific manner but rather in a very generic manner, independent of their sequence or target, that is an siRNA targeting one gene works just as well as an siRNA targeting some other gene in the context of suppressing blood vessel growth, which is the pathological hallmark of macular degeneration in its late stage, so what our work shows is that first, all siRNAs presumably can suppress blood vessel growth in macular degeneration regardless of what they target and two, although at first glance this effect might prove to be beneficial, we have also found that siRNAs can cause death of other cells within the eye, thereby raising potential adverse consequences of this kind of therapy.

Michael Hopkin: Would you say on balance that your research means it might be easier to make these drugs or is it going to be more difficult?

Jayakrishna Ambati: What our research points out is that these types of drugs have a mechanism of action that is entirely different than what is purported to be and therefore it raises the question of adverse effects; if these effects in mice are seen in people. Therefore we believe that clinical trials of these drugs should be approached with great caution.

Michael Hopkin: And is this going to be a problem for people trying to develop any sorts of RNA-based drugs?

Jayakrishna Ambati: Yes, I believe so, because we found that siRNAs targeting any sequence all activate this alternate pathway and therefore in order to realize the promise of specific gene targeting using siRNA therapy, one must take this alternate mechanism of action into account and develop means to modify siRNAs, so that they no longer act via this alternate pathway. On balance, I think, what this research tells us is that we have a new way of attacking blood vessel growth using siRNAs in a generic fashion. At the same time, prudence dictates that we examine carefully how these therapies actually work and understand all their effects both intended and unintended. What this research really tells us is there are no quick fixes as far as jumping into the clinic with siRNA therapy.

Kerri Smith: Jayakrishna Ambati of the University of Kentucky who has been unravelling the mechanisms of RNAi to treat eye disease. The eye is an organ that creationists often sight as evidence for a divine creator, saying that is too sophisticated to have evolved. This specious argument more often than not infuriates biologists, but our podium speaker at this week wants to see some moderation in discussions between scientists and the religious. Here is Eugenie Scott Director of the National Centre for Science Education in California.

Eugenie C. Scott: I direct an American NGO that monitors the creationism and evolution controversy. We want evolution to be taught in science class, not creationism. I spend a lot of my time coping with people who believe that God specially created the whole universe as we see it today; they don't want evolution taught in schools. Many allies of mine on the evolution side of this controversy end up lashing out at religion in frustration. I think they are missing the point. Religion per se isn't the enemy; the enemy is any unwillingness to be rational and to look at evidence. People of faith can be rational; non-believers can be irrational. There are many sources of irrationality. One's heartfelt ideologies can easily cause one to overlook what's out there in favour of what one wishes was out there. Our ideologies shape how we perceive the world and interact with it. Everyone has them and they are not necessarily bad, unless they are so rigid they get in the way of altering one's opinion in the face of evidence. Religious ideologies like creationism can blind one to seeing evidence, to believe that the world is 6000 years old, you can't just have to ignore vast amounts of evidence from geology, physics, and chemistry, but some religious ideologies do not have this problem. Catholics and mainstream Protestants have a long history of accommodating faith to the evidence of science. Today very few Christians believe the geocentric bible trumps scientific evidence of heliocentrism and most Christian theology likewise accepts evolution as a way through which God creates. So I have many Christian pro-evolution allies who want evolution taught without qualifications in science class. They oppose creationism as both bad science and errant theology nor is it only religious ideologies that can get in the way of a clearheaded assessment of evidence. Political, economic, and social ideologies like Marxism, Libertarianism, Capitalism, Racism, Feminism, Veganism, and Environmentalism may destroy one's ability to reason logically and to assess empirical evidence. The consequences can be disastrous. It was Marxist ideology, not religion that promoted the pseudoscientific so called genetics of Lisenko, which lead to the collapse of soviet agriculture and consequent famine, so I suggest that my religion critical allies in the creationism and evolution controversy look at the evidence. There are many people of faith who admire science, who accept evolution and who want students to be taught modern science. I am happy to work with them. After all anything else would be irrational.

Adam Rutherford: Eugenie Scott from the NCSC. Sticking with the evolutionary theme, a fundamental question in biology is whether an organism's complexity affects its ability to evolve. This is the so-called cost of complexity. It follows on from the observation, that a single alteration in DNA can have a number of distinct, but not necessarily beneficial effects. For example a mutation in one gene could result in changes in both heart tissue and the eye, this phenomenon is known as pleiotropy. A new report suggests that pleiotropic effects do not in fact make evolution more costly. I spoke to lead author Gunter Wagner and started by asking why pleiotropy has posed a problem for the evolution and complexity. Nature 452, 470–472 (27 March 2008)

Gunter P. Wagner: If a single change is affecting many aspects of the phenotype then the likelihood that all these effects together are actually advantageous becomes very small. So if you think of tuning a microscope and you change one knob and it changes the alignment of the light beam and distance of the lens to the object all at the same time, its hard to come to a well-tuned microscope. So the intuition is that the more widespread effects are, the more damage on average they do and the less likely it is to get any improvement.

Adam Rutherford: Okay and that has led to the concept- the so called cost of complexity. Can you just explain what that is?

Gunter P. Wagner: The various arguments that essentially all come to the conclusion that it might be difficult to improve complex organisms by random genetic change, some are the ones that say if pleiotropic effects are as widespread as the intuition would tell us, then the probability to improve an organism becomes very small. Another type of argument was actually a mathematical model which made the assumption that the more complex an organism is, the smaller the effects gets paired for each character itself. So all of those models and predictions are based on assumptions of how genetic effects work and how they are distributed across characters and that was not known for until we had now these techniques, big enough data sets and this is the study where a really big data set could be analyzed and we could ask those questions not theoretically but on empirical basis.

Adam Rutherford: So in the new study, your results have shown that the cost of complexity probably isn't the factor.

Gunter P. Wagner: Perhaps the most cautious conclusion would be to say that organisms like mice at least found a way around those problems. So their genome seems to be organized in a way that many of these problems - predicted problems, are not expected to occur. So that the two main findings, one is that most of the genes that have been mapped affect a relatively small number of characters, unlike some model assumptions and the other is that the effects on different characters actually accumulate and they don't cancel each other out, as other theories have predicted.

Adam Rutherford: Tell us a little bit about the methodology because looking at the paper there is some quite classical genetics in there really.

Gunter P. Wagner: Right there is not much really brand new technology that is used in this study. It is a technique that has been used for, you know, I think one or two decades, quite routinely but what is unique about that data set is that nobody has done that, as extensive a study as my colleagues at Washington University and they made looking at simultaneously 70 different skeletal traits in mouse and mapped all the genomic regions that affect those and you need these very extensive sampling of the phenotype in order to make statements about, you know, how broad gene effects are and how they, you know, combine from different characters.

Adam Rutherford: Overall, the conclusion is that, the idea here is that there is a cost of complexity turns out that with a new large data set doesn't seem to be as significant a factor in reducing complexity as we previously thought.

Gunter P. Wagner: Right. That is, that many of the assumptions from theoretical models that led to this cost of complexity concept have proved simply wrong and the way probably we should think about it is that, the genomes evolved in a way, I mean, we don't know why and how, but evolved an organization that avoids those problems of cost of complexity.

Adam Rutherford: Gunter Wagner from Yale University.

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Kerri Smith: Finally this week, we unearth the remains of the earliest hominin in Europe. At a well-known fossil hunting site in northern Spain a group of palaeoanthropologists have found a part of a jawbone or a mandible alongside some stone tools and animal remains. They've been able to accurately date the remains to about 1.2 million years old, about 400,000 years before the earliest known fossils to date. Co-author José María Bermúdez de Castro described what the team found. Nature 452, 465–469 (27 March 2008)

José María Bermúdez de Castro: In the past 5 years, we found some artefacts made on flint at the Sima del Elefante cave, which have the most ancient archaeological reveals of Sierra de Atapuerca. We assume that these artefacts were made by hominins probably more than 1 million years ago. Finally, we have found the symphysis of a well-preserved human mandible with some in situ teeth. The symphysis is the anterior region of the mandible where we have developed the chin.

Kerri Smith: What did we think was the oldest hominin in Europe before you made this discovery?

José María Bermúdez de Castro: Before this finding, the oldest hominin in Europe was found at the Sierra de Atapuerca as well. In 1994, we found more than a 100 human fossil remains at the level 6 of the Gran Dolina cave site, which is 200 meters away from Sima Del Elefante, very near Sima del Elefante. These fossils are between 8 and 900,000 years old and in 1997, they were included in a new homo species Homo antecessor.

Kerri Smith: And this jawbone, this mandible that you have found you think that is also an example of Homo antecessor?

José María Bermúdez de Castro: Yes may be, but for the moment we have attributed to the Homo antecessor provisionally.

Kerri Smith: And what is this finding that predates the other findings then by, you know, 400,000 years reveal about when hominins arrived in Europe, and what they were like?

José María Bermúdez de Castro: Well, there are some sites at the south of Spain and in Italy that have yielded some stone artefacts, which may be older than 1 million years old, but human remains never were found at these sites, finally they have appeared in Spain at Sierra de Atapuerca. With the evidence we have at this moment it is not possible to make a picture of the first Europeans, but some anatomical features of this mandible reveal that they probably were not very different from the hominins found at the Dmanisi site in the Republic of Georgia where we have the evidence of the first out of Africa demographic expansion.

Kerri Smith: So another thing this jawbone really gives us more concrete evidence than we had from stone tool findings, that hominins occupied this site in Spain over 1 million years ago. I've got Nature editor Henry Gee in the studio with me, to provide us with a bit of context to the new find. Henry, tell us first of all a bit about the Atapuerca site where these fossils where found?

Henry Gee: The Atapuerca site is not really just a site, it is a whole mountain massive, it is a large region in which there are a lot of different caves which have been explored at various times and they span a great range of ages, so it is not like it is one tiny hole in the ground, there are a whole range of caves which have produced different kinds of hominins, different tools over quite some years.

Kerri Smith: So, palaeoanthropologists have been kind of interested in this region for really quite some time, how come we are still finding specimens there?

Henry Gee: Well, it is such a big place and there are lots of caves and lots of places still to look. Like any of these places, it is a kind of a potholing paradise, the first one that came to notice the Sima de los Huesos: The pit of bones is an extremely difficult hole in the ground to get to. They had to be really like cavers to get down into the cave and pull the stuff up, it was really quite remarkable. Some of the caves there are rather different and more accessible, but it is not just one cave, it is more of a way of life I think.

Kerri Smith: So that's some of the context then to where these fossils were found. Turning to the implications of the new findings, what do these new findings suggest to us about the Homo Diaspora things that we did not know about it before?

Henry Gee: I think it's rather head-scratching actually a very important part of the fossil find is the date which is quite well constrained between 1.1 and 1.2 million years old. The researchers assign this find provisionally to a species called Homo antecessor, which is being claimed to be the last common ancestor perhaps of modern humans and Neanderthals who's whereabouts' also debated and has also been described, as far as I know, only from Atapuerca. There are older hominin remains far to the east in the Republic of Georgia, Dmanisi. These are may be 1.8 million but they are very much more primitive than the hominin from Atapuerca, although as a group they all fall into a kind of early modern Homo group. It is a particularly difficult and exciting part of paleoanthropology at the moment, working out how the first humans came out of Africa, and that is not Homo sapiens but the earlier Diaspora how humans, which we would call Homo erectus first came out of Africa 1.8 to 2 million years ago. It is a field that has now blown wide open by discoveries such as Homo floresiensis, for example, which was a little creature that lived as recently as 14,000 years ago in Indonesia. Some people think that was a dwarf Homo erectus, some people think it was a pathological modern human, but the researchers themselves tend to think that was an extremely early radiation of humans or pre-humans, Australopithecine humans from Africa, so the whole business about migration out of Africa is wide open at the moment, its actually very exciting – who knows what is going to happen.

Kerri Smith: Editor Henry Gee there and before him José María Bermúdez de Castro of the National Centre for Research on Human Evolution in Burgos Spain. That's all from us this week. Remember that you can win an iPod Touch in our Sound of Science competition, which closes on the 31st of March, so only a few days left to enter.

Adam Rutherford: You just need to identify three sounds taken from the podcast archives from autumn last year, to spare you along, here they are again.

[Music plays with three different sounds]

Adam Rutherford: So identify those three sounds and follow the link from http://www.nature.com/nature/podcast. I'm Adam Rutherford.

Kerri Smith: And I'm Kerri Smith. Good Luck and thanks for listening.

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